CN101043887A - 2-(aryl)azacyclylmethyl carboxylates, sulfonates, phosphonates, phosphinates and heterocycles as s1p receptor agonists - Google Patents

2-(aryl)azacyclylmethyl carboxylates, sulfonates, phosphonates, phosphinates and heterocycles as s1p receptor agonists Download PDF

Info

Publication number
CN101043887A
CN101043887A CNA2005800362656A CN200580036265A CN101043887A CN 101043887 A CN101043887 A CN 101043887A CN A2005800362656 A CNA2005800362656 A CN A2005800362656A CN 200580036265 A CN200580036265 A CN 200580036265A CN 101043887 A CN101043887 A CN 101043887A
Authority
CN
China
Prior art keywords
disease
phenyl
chemical compound
alkoxyl
syndrome
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CNA2005800362656A
Other languages
Chinese (zh)
Inventor
J·J·哈尔
严林
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Publication of CN101043887A publication Critical patent/CN101043887A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/18—Antioxidants, e.g. antiradicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Oncology (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Communicable Diseases (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Endocrinology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Obesity (AREA)
  • Neurosurgery (AREA)
  • Biochemistry (AREA)
  • Pain & Pain Management (AREA)
  • Emergency Medicine (AREA)
  • Transplantation (AREA)
  • Virology (AREA)

Abstract

The present invention encompasses compounds of Formula I: as well as the pharmaceutically acceptable salts thereof. The compounds are S1P<SUB>1</SUB>/Edg1 receptor agonists and thus have immunosuppressive, anti-inflammatory and hemostatic activities by modulating leukocyte trafficking, sequestering lymphocytes in secondary lymphoid tissues, and enhancing vascular integrity. The invention is also directed to pharmaceutical compositions containing such compounds and methods of treatment or prevention.

Description

2-(aryl) azacyclo-methyl carboxylic acids ester, sulphonic acid ester, phosphonate ester, phosphinate and heterocyclic compound as the S1P receptor stimulating agent
Background of invention
The present invention relates to is S1P 1/ Edg1 receptor stimulating agent and therefore by the lymphocyte in regulation and control leukocyte flux, the chelating secondary lymphoid tissue with improve the chemical compound that vascular integrity has immunosuppressant, antiinflammatory and styptic activity.The invention still further relates to the pharmaceutical composition and treatment or the prevention method that comprise this compounds.
Shown that immunosuppressant and antiinflammatory can be used for many autoimmune and chronic inflammatory disease, comprise systemic lupus erythematosus, chronic rheumatoid arthritis, type i diabetes, inflammatory bowel, biliary cirrhosis, uveitis, multiple sclerosis and other disease such as Crohn disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmunity myositis, the Wei Genashi granuloma, ichthyosis, Ge Leifusishi oculopathy, atopic dermatitis and asthma, chronic lung disease, acute lung injury, adult respiratory distress syndrome and sepsis.Prove that also it can be used as a part that is used for the treatment of cancer, lymphoma and leukemic chemotherapy regimen.
Though the pathogenetic basis of each disease may be different fully in these diseases, it a large amount of autoantibodys, autoreactivity lymphocyte all occur and/or relates to autarcetic cell-stimulating.Such autoreactivity may partly be to cause at the homeostatic control that it turns round down owing to having lost normal immune system.Similarly, after bone marrow or organ transplantation, host's lymphocyte is discerned this external tissue antigen and is begun to produce cell and the body fluid response, comprises antibody, cytokine and cytotoxic lymphocyte, and it has caused transplant rejection.
A kind of final result of autoimmune or repulsion process is that inflammatory cell and the medium that discharges owing to it causes disorganization.Antiinflammatory such as NSAID mainly work by effect or the secretion of blocking these media, but it can't change the amynologic basis of said disease.On the other hand, cytotoxic agent such as cyclophosphamide work in a kind of non-specific mode, thereby make and not only to have cut off normal response but also cut off the autoimmune response.Because infecting is himself immune disease, so the patient who treats with such nonspecific immunosuppressive agent dies from infection in fact possibly.
Cyclosporin A is a kind of medicine that is used to prevent the transplant organ repulsion.FK-506 is that another kind is approved for the medicine that prevention transplant organ repulsion and particularly liver transplantation are repelled.Cyclosporin A and FK-506 make it to transfer its huge bank that repels the natural protective agent of transplantability foreign protein by the immune system that suppresses body to work.Cyclosporin A is approved for the serious psoriasis of treatment and has been used for the treatment of atopic dermatitis by some European administrative organizations (Europeanregulatory agencies) approval.
Though can effectively postpone or suppress transplant rejection, known cyclosporin A and FK-506 can cause several side effect of occurring do not wished, comprise nephrotoxicity, neurotoxicity and gastrointestinal upset.Therefore, still need and very wish a kind of immunosuppressant that does not have these side effect of development.
Inhibitive ability of immunity compound F 17-hydroxy-corticosterone TY720 is the lymphocyte chelating agen that is carrying out clinical trial at present.It is the chemical compound of effective sphingosine 1-phosphate receptor agonist that FTY720 is metabolised in mammalian body.The excitement of sphingosine 1-phosphate receptor is being regulated and control the leukocyte flux, is not being had lymphocyte to exhaust to have induced lymph node under the situation of (lymphodepletion) and send the chelating of Ilyushin class medium-sized lymphocyte (T-cell and B-cell) and destroyed the architecture of spleen, thereby has disturbed T cell dependency and non-T cell dependency antibody to respond.By improving endothelium integrity and the inhibition vascular lesion as the immune system activation consequence, the S1P receptor stimulating agent also has antiinflammatory property.Such immunosuppressant and antiinflammatory action are desirable aspect following: the repulsion behind the prevention of organ transplant, the treatment autoimmune conditions, and the treatment aspect vascular integrity, have cause of disease defective for example acute lung injury of disease, adult respiratory distress syndrome and sepsis,-referring to Groeneveld, A.B.J.2003.Vascular Pharm.39:247-256.
Sphingosine 1-phosphate is a kind of by hematopoietic cell secretion and the bioactive sphingolipid metabolism thing that stores and discharged by the platelet that is activated.Yatomi，Y.，T.Ohmori，G.Rile，F.Kazama，H.Okamoto，T.Sano，K.Satoh，S.Kume，G.Tigyi，Y.Igarashi，and Y.Ozaki.2000.Blood.96：3431-8。Its agonist that can be used as the protein-coupled receptor family of G is regulated hyperplasia, differentiation, survival and motility.Fukushima, N., I.Ishii, J.J.A.Contos, J.A.Weiner, and J.Chun.2001.Lysophospholipidreceptors.Annu.Rev.Pharmacol .Toxicol.41:507-34; Hla, T., M.-J.Lee, N.Ancellin, J.H.Paik, and M.J.Kluk.2001. Lysophospholipid Receptor (Lysophospholipids Receptor) .Annu.Rev.Pharmacol.Toxicol.41:507-34; Hla, T., M.-J.Lee, N.Ancellin, J.H.Paik, and M.J.Kluk.2001. lysophosphatide-receptor enlightenment (Lysophospholipids-Receptor revelations) .Science.294:1875-1878; Spiegel, the function of the new sphingosine-1-phosphate ester of S. and S.Milstien.2000. receptor family (Functions of a new family of sphingosine-1-phosphatereceptors) .Biochim.Biophys.Acta.1484:107-16; Pyne, S. and sphingosine 1-phosphate (the Sphingosine 1-phosphate signalling via the endothelialdifferentiation gene family of G-protein coupled receptors) .Pharm.﹠amp that signals by the endothelial differentiation gene family of the protein-coupled receptor of G-of N.Pyne.2000.; Therapeutics.88:115-131.Five kinds of sphingosine 1-phosphate receptor (S1P have been identified 1, S1P 2, S1P 3, S1P 4And S1P 5, be also referred to as endothelial differentiation gene Edg1, Edg5, Edg3, Edg6, Edg8), it extensively is distributed in cell and the tissue and is well preserved (seeing Table) in people and rodent kind body.Caused the signal transduction that is undertaken by Gq-, Gi/o, G12-, G13-and Rho-dependent pathway with combining of S1P receptor.Shown the inductive S1P of part 1And S1P 3The activation angiogenesis, the chemotaxis that have promoted to be undertaken by Rac-and Rho-and adhere to articulation set, see Lee, M.-J., S.Thangada, K.P.Claffey, N.Ancellin, C.H.Liu, M.Kluk, M.Volpi, R.I.Sha ' afi, and T.Hla.1999.Cell.99:301-12.S1P improves the endothelial barrier integrity in the following manner: via the S1P receptor, mainly be that S1P1 assembles cortex actin cell skeletal structure and strengthens cell: cell is connected and cell: the extracellular matrix interaction-, referring to Garcia, J.G.N, F.Liu, A.D.Verin, A.Birukova, M.A.Dechert, W.T.Gerthoffer, J.R.Bamburg, D.English, 2001.J.Clin.Invest.108:689-701, and S1P receptor stimulating agent, comprise FTY720, in mice, can suppress inductive vascular permeability, referring to Sanchez by VEGGF, T., T.Estrada-Hernandez, J.-H.Paik, M.-T.Wu, K.Venkataraman, V.Brinkmann, K.Claffey, and T.Hla.2003.J.Biol.Chem.278:47281-47290.
Use sphingosine 1-phosphate to animal and induced the whole body peripheral blood lymphocyte to be chelated in the secondary lymphoid organ, thereby produced immunosuppressant useful on the therapeutics, referring to Mandala, S., R.Hajdu, J.Bergstrom, E.Quackenbush, J.Xie, J.Milligan, R.Thornton, G.-J.Shei, D.Card, C.Keohane, M.Rosenbach, J.Hale, C.L.Lynch, K.Rupprecht, W.Parsons, H.Rosen.2002.Science.296:346-349.But sphingosine 1-phosphate also has some and limits its cardiovascular and bronchoconstriction effect as the practicality of therapeutic agent.The intravenous administration of sphingosine 1-phosphate has reduced heart rate, ventricular systole and the blood pressure of rat, referring to Sugiyama, and A., N.N.Aye, Y.Yatomi, Y.Ozaki, and K.Hashimoto.2000.jpn.J.Pharmacol.82:338-342.In Human airway smooth muscle's cell, sphingosine 1-phosphate is being regulated and control the growth of contraction, cell and is being promoted remodeling in cytokine generation, airway inflammation and the asthma of bronchoconstriction, referring to Ammit, A.J., A.T.Hastie, L.C.Edsall, R.K.Hoffman, Y.Amrani, V.P.Krymskaya, S.A.Kane, S.P.Peters, R.B.Penn, S.Spiegel, R.A.Panettieri.Jr.2001, FASEB are J.15:1212-1214.It is relevant that this effect of not wishing the sphingosine 1-phosphate that occurs and its non-selectivity ground all have an effective agonist activity to all S1P receptors.
The present invention includes is S1P 1The selectivity of/Edg1 receptor stimulating agent is higher than S1P 3The chemical compound of/Edg3 receptor.S1P 1/ Edg1 receptor selective agonists has the advantage that is better than present therapy and has enlarged the treatment window of lymphocyte chelating agen and blood vessel integrity agent, can tolerate higher dosage and improve its effectiveness as monotherapy thereby the expansion of treatment window is feasible.
Though the main application of immunosuppressant and antiinflammatory is to be used for the treatment of bone marrow, organ and transplant rejection, but other of this compounds used and also to be comprised and can be used for treatment of arthritis, particularly rheumatoid arthritis, insulin and noninsulindependent diabetes, multiple sclerosis, psoriasis, inflammatory bowel, Crohn disease, lupus erythematosus, asthma, allergy, chronic lung disease, acute lung injury, adult respiratory distress syndrome, sepsis or the like.
Therefore, the object of the present invention is to provide than safer more effective immunosuppressant of prior art chemical compound and vascular integrity chemical compound.Describe in detail by this paper, these and other objects of the present invention will be tangible for those of ordinary skills.
The general introduction of S1P receptor
Title Synonym The G albumen of coupling MRNA expresses
S1P 1 Edg1，LP B1 G i/o Extensively distribute endotheliocyte
S1P 2 Edg5，LP B2， AGR16，H218 G i/o，G q， G 12/13 Extensively distribute vascular smooth muscle cell
S1P 3 Edg3，LP B3 G i/o，G q， G 12/13 Extensively distribute endotheliocyte
S1P 4 Edg6，LP C1 G i/o Lymphoid tissue, lymphocyte series
S1P 5 Edg8，LP B4， NRG1 G i/o Brain, spleen
Summary of the invention
The present invention includes formula I chemical compound:
Figure A20058003626500171
And officinal salt.The compounds of this invention is S1P 1/ Edg1 receptor stimulating agent and therefore by the lymphocyte in regulation and control leukocyte flux, the chelating secondary lymphoid tissue with improve vascular integrity and have immunosuppressant, antiinflammatory and styptic activity.The invention still further relates to the pharmaceutical composition and treatment or the prevention method that comprise this compounds.
Detailed Description Of The Invention
The present invention includes formula I chemical compound
Figure A20058003626500172
Or its officinal salt, wherein:
N is 0,1 or 2;
M is 0,1 or 2, and when m was 0, the A Direct Bonding was on the azetidine shown in the formula I (n=0), pyrrolidine (n=1) or piperidines (n=2) like this;
R 1, R 2, R 3And R 4Be independently selected from :-H ,-F, C 1-C 4Alkyl, C 1-C 4Perfluoroalkyl ,-Cl ,-Br, C 1-C 8Alkoxyl and-OCF 3
R 5And R 6Be independently selected from :-H ,-OH ,-F, C 1-C 4Alkyl and C 1-C 4Perfluoroalkyl;
R 7Be selected from: phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl and thienyl, each described group is optional to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-CN ,-OH ,-NR 8R 9,-NO 2, phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Alkoxyl, C 3-C 6Cycloalkyloxy, C 1-C 6Alkylthio group and C 2-C 6Acyloxy,
Wherein said phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Alkoxyl, C 3-C 6Cycloalkyloxy, C 1-C 6Alkylthio group and C 1-C 6Acyloxy is optional respectively to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-OH and C 1-C 5Alkoxyl;
R 8And R 9Be independently selected from: C 1-C 6Alkyl, C 1-C 6Alkenyl and C 1-C 6Alkynyl, each described group is optional to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-OH and C 1-C 5Alkoxyl, perhaps
R 8And R 9Can form the optional saturated monocycle that contains 1 or 2 oxygen atom with the nitrogen-atoms that they connected with 3-8 atom, described ring optional by 1-3 be independently selected from following substituent group replacement :-F ,-Cl ,-Br ,-I ,-OH and C 1-5Alkoxyl;
X, Y and Z are independently selected from :-C=,-CH-,-O-,-N=,-NH-,-N (R 10)-and-S-, the gained ring is fragrant heterocycle like this;
R 10Be selected from: C 1-C 6Alkyl, C 1-C 6Alkenyl and C 1-C 6Alkynyl, each described group is optional to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-OH and C 1-C 5Alkoxyl;
A is selected from :-CO 2H ,-PO 3H 2,-PO 2H 2,-SO 3H ,-CONHSO 2R 11,-PO (R 11) OH,
Figure A20058003626500191
R 11Be selected from: C 1-C 4Alkyl, phenyl ,-CH 2OH and CH (OH)-phenyl; And
Each R 12Be independently selected from :-H and-CH 3
One embodiment of the invention comprise that wherein A is-CO 2The formula I chemical compound of H.
Another embodiment of the invention comprises that n wherein is 1 formula I chemical compound.
Another embodiment of the invention comprises that m wherein is 1 formula I chemical compound.
Another embodiment of the invention comprises the formula I chemical compound that is defined as follows: wherein X is-N=, and Y is-N=, and Z is-O-that formed like this ring is 1,2,4- diazole.
Another embodiment of the invention comprises the formula I chemical compound that is defined as follows: R wherein 7Be phenyl, described phenyl is optional to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-CN ,-OH ,-NR 7R 8,-NO 2, phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Alkoxyl, C 3-C 6Cycloalkyloxy, C 1-C 6Alkylthio group and C 2-C 6Acyloxy,
Wherein said phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Alkoxyl, C 3-C 6Cycloalkyloxy, C 1-C 6Alkylthio group and C 1-C 6Acyloxy is optional respectively to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-OH and C 1-C 5Alkoxyl.
Another embodiment of the invention comprises the chemical compound of formula Ia representative
Figure A20058003626500201
Or its officinal salt, wherein:
P is 0,1 or 2;
R aBe selected from: phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 1-C 6Alkoxyl and C 3-C 6Cycloalkyloxy, wherein said phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 1-C 6Alkoxyl and C 3-C 6Cycloalkyloxy is optional respectively to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I and-OH; And
R bBe selected from :-F ,-Cl ,-Br ,-I ,-CN ,-CH 3,-OCH 3,-CF 3, acetenyl ,-NO 2With-NH 2
One embodiment of the invention comprise the formula Ia chemical compound that is defined as follows: wherein p is 0 or 1, and R bBe selected from :-F ,-Cl and-CF 3
Another embodiment of the invention comprises the formula Ia chemical compound that is defined as follows: R wherein aBe selected from: C 3-C 5Alkyl, cyclopenta, cyclohexyl, C 2-C 4Alkoxyl, cyclopentyloxy and cyclohexyloxy, each described group is optional to be replaced by 1-3 fluorine.
In the following example, further illustrate the present invention.
The present invention also comprises a kind of method for the treatment of immunoregulatory abnormality in the mammalian subject that needs such treatment, and described method comprises with the amount of the described immunoregulatory abnormality of effective treatment uses formula I chemical compound for described patient.
Comprise that in this embodiment wherein said immunoregulatory abnormality is to be selected from: the autoimmunity of systemic lupus erythematosus, chronic rheumatoid arthritis, type i diabetes, inflammatory bowel, biliary cirrhosis, uveitis, multiple sclerosis, Crohn disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmunity myositis, Wei Genashi granuloma, ichthyosis, Ge Leifusishi oculopathy and asthma or the said method of chronic inflammatory disease.
Comprise also that in this embodiment wherein said immunoregulatory abnormality is the said method of bone marrow or organ-graft refection or graft versus host disease.
Comprise also that in this embodiment wherein said immunoregulatory abnormality is selected from the said method of following disease: the transplanting of organ or tissue; the graft versus host disease that causes by transplanting; comprise rheumatoid arthritis; systemic lupus erythematosus is in interior autoimmunity syndrome; struma lymphomatosa; multiple sclerosis; myasthenia gravis; type i diabetes; uveitis; posterior uveitis; allergic encephalitis; glomerulonephritis; the metainfective autoimmune disease that comprises rheumatic fever and metainfective glomerulonephritis; inflammatory and hyperplasia dermatoses; psoriasis; atopic dermatitis; contact dermatitis; eczematoid dermatitis; seborrheic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; nodular vasculitis; erythema; eosinophilia on the skin; lupus erythematosus; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; the uveitis relevant with Behcet; keratitis; herpetic keratitis; keratoconus; dystrophia epithelialis corneae (dystrophia epithelialis corneae); corneal leukoma; ocular pemphigus; Mooren's ulcer; scleritis; Ge Leifusishi oculopathy (Graves ' opthalmopathy); Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergy; the reversibility obstructive airway diseases; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or chronic and refractory asthma; asthma in late period (late asthma) and airway hyperreactivity; bronchitis; gastric ulcer; the vascular lesion that causes by ischemic disease and thrombosis; ischemic bowel disease; inflammatory bowel; necrotizing enterocolitis; the small intestinal infringement relevant with thermal burn; celiac disease; proctitis; the eosinophilic gastroenteritis; mastocytosis; Crohn disease; ulcerative colitis; migraine; rhinitis; eczema; interstitial nephritis; goodpasture syndrome; hemolytic uremic syndrome; diabetic nephropathy; the sugar polymyositis; guillain-Barre syndrome; Meniere; polyneuritis; polyneuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's disease; simple property erythroid aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; erythrocyte takes place can not; osteoporosis; sarcoidosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; the vitiligo vulgaris disease; ichthyosis vulgaris; photo-allergy sensitivity; cutaneous T cell lymphoma; arteriosclerosis; atherosclerosis; arteritis syndrome; polyarteritis nodosa; myocardosis; scleroderma; the Wei Genashi granuloma gangraenescens; sjogren's syndrome; obesity; the eosinocyte fascitis; gum; periodontal tissue; the infringement of alveolar bone; substantia ossea dentis; glomerulonephritis; male pattern alopecia or senile alopecia (by preventing alopecia or providing the hair rudiment and/or generation of promotion hair and natural on-off cycles of hair growth); muscular dystrophy; the assorted Reye syndrome of pyoderma and match; addisonian syndrome; in protection; the ischemia-reperfusion damage of the organ that takes place when transplanting or ischemic disease; endotoxin shock; pseudomembranous colitis; the colitis that causes by medicine or radiation; the ischemic acute renal insufficiency; chronic renal insufficiency; by lung-oxygen or drug induced toxinosis; pulmonary carcinoma; emphysema; cataract; arc-welder's disease; retinitis pigmentosa; senile degeneration of macula; the vitreal cicatrization; cornea highly basic burn; erythema multiforme dermatitis (dermatitiserythema multiforme); linear IgA ballous dermatitis and cementdermatitis; gingivitis; periodontitis; sepsis; pancreatitis; the disease that causes by environmental pollution; old and feeble; carcinogenesis; cancerometastasis and altitude sickness; discharge the disease that causes by histamine or leukotriene-C4; Behcet; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial hepatectomy; acute severe hepatitis; the necrosis that causes by toxin; viral hepatitis; shock; or anoxia; the B-viral hepatitis; non--A/ is non--hepatitis B; liver cirrhosis; alcoholic cirrhosis; liver failure; fulminant hepatic failure; the liver failure of late onset (late-onsethepatic failure); " acute-on-chronic " liver failure; the reinforcement of chemotherapy effect; cytomegalovirus infection; HCMV infects; AIDS; cancer; alzheimer disease; wound and chronic bacterial infection.
Comprise also in this embodiment that immunoregulatory abnormality wherein is selected from the said method of following disease:
1) multiple sclerosis,
2) rheumatoid arthritis,
3) systemic lupus erythematosus,
4) psoriasis,
5) repulsion of transplant organ or tissue,
6) inflammatory bowel,
7) malignant tumor in lymph source,
8) acute and chronic lymphocytic leukemia and lymphoma and
9) insulin and noninsulindependent diabetes.
The present invention comprises that also a kind of inhibition needs immune method in the immunosuppressant mammalian subject, and described method comprises the formula I chemical compound of using the immunosuppressant effective dose to described patient.
The present invention also comprises a kind of pharmaceutical composition that comprises formula I chemical compound and pharmaceutically suitable carrier.
The present invention also comprises a kind of method for the treatment of respiratory disorder in the mammalian subject that needs such treatment or disease, and described method comprises with the amount that can effectively treat described respiratory disorder or disease uses formula I chemical compound for described patient.Comprise that in this embodiment wherein said respiratory disorder or disease are selected from following said method: asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, the acidophil granuloma, respiratory syncytial virus bronchiolitis, bronchiectasis, idiopathic pulmonary fibrosis, acute lung injury and obstructive bronchiolitis are organized pneumonia (bronchiolitis obliteransorganizing pneumonia).
The present invention comprises that also treatment relates to the disease of vascular integrity or the method for disease in the patient of these needs is arranged, wherein said disease or disease are selected from: angioedema, nodular vasculitis, the blood vessel injury that causes by ischemic diseases and thrombosis, ischemic enteropathy, inflammatory bowel, necrotizing enterocolitis, the damage of intestines that causes with thermal burn, arteriosclerosis, atherosclerosis, aortitis syndrome, in preservation, the ischemia reperfusion injury that takes place during transplanting or the ischemic diseases, endotoxin shock, pseudomembranous colitis, by medicine or radioactive colitis, ischemic acute renal insufficiency, chronic renal insufficiency, by lung oxygen or drug-induced toxinosis, sepsis, pancreatitis, discharge the disease that causes by histamine or leukotriene-C4, the necrosis that causes by toxin, viral hepatitis, shock or anoxia, senile dementia and wound, described method comprise the formula I chemical compound of using the amount that can effectively treat disease or disease to described patient.
The present invention comprises that also treatment has among the patient of these needs the method with brain or pulmonary edema diseases associated or disease, and described method comprises the formula I chemical compound of using the amount that can effectively treat disease or disease to described patient.This embodiment comprises and is selected from following disease or disease: shock, sepsis, adult respiratory distress syndrome and cerebral edema.
Comprise also that in this embodiment wherein said patient also suffers from the said method of respiratory disorder or disease.
Comprise also that in this embodiment wherein said patient also suffers from the said method of cardiovascular disease or disease.
Except as otherwise noted, use following definition to describe the present invention.
When occurring in the formula of nitrogen-atoms in this description, should be understood that to exist and satisfy enough hydrogen atoms or the substituent group that this nitrogen-atoms is tired.
Term " halogen " or " halo " comprise F, Cl, Br and I.
Term " alkyl " refer to have shown in the straight or branched structure and the combination thereof of carbon number.Therefore, C for example 1-6Alkyl comprise methyl, ethyl, propyl group, 2-propyl group, the second month in a season-and tert-butyl, butyl, amyl group, hexyl, 1,1-dimethyl ethyl, cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.
Term " alkenyl " be meant have shown in the straight or branched structure with at least one carbon-to-carbon double bond of number carbon atom or its combination, wherein hydrogen can be substituted by other carbon-to-carbon double bond.C 2-6Alkenyl comprises for example vinyl, acrylic, 1-methyl ethylene, cyclobutenyl etc.
Term " alkynyl " be meant have shown in the straight or branched structure with at least one carbon-to-carbon triple bond or its combination of number carbon atom.C 3-6Alkynyl comprises for example propinyl, 1-methylacetylenyl, butynyl etc.
Term " alkoxyl " refer to have shown in the alkoxyl of straight chain, side chain or cyclic configuration of carbon number.For example, C 1-6Alkoxyl comprises methoxyl group, ethyoxyl, propoxyl group, isopropoxy etc.
Term " alkylthio group " refer to have shown in the alkylthio group of straight chain, side chain or cyclic configuration of carbon number.For example, C 1-6Alkoxyl comprises methyl mercapto, rosickyite base, iprotiazem base etc.
Term " cycloalkyl " refer to have shown in the randomly combination of carbon number have the list of straight or branched structure-, two-or three-ring structure.The example of cycloalkyl comprises cyclopropyl, cyclopenta, suberyl, adamantyl, cyclododecane ylmethyl, 2-ethyl-1-bicyclo-[4.4.0] decyl, cyclobutylmethyl, cyclopropyl methyl etc.
Term " cycloalkyloxy " is meant the cycloalkyl as defined above that is connected with molecule by oxygen atom (cycloalkyl-O), and comprise for example cyclopentyloxy, cyclo propyl methoxy etc.
Term " acyl group " is meant by removing hydroxyl derived from the organic acid organic group, and have general formula R-C (O)-, wherein R is the straight or branched alkyl, described Ah's files are with carbon atom number shown in carbonyl has.For example, C 2-4Acyl group comprises acetyl group, propiono and bytyry.Term " acyloxy " is meant the acyl group as defined above that is connected with molecule by oxygen atom (acyl group-O), and comprise for example acetoxyl group etc.
Phrase " R 8And R 9Can form the optional saturated monocycle that contains 1 or 2 oxygen atom with the nitrogen-atoms that they connected with 3-8 atom " be meant for example pyrrolidine, piperidines, morpholine, azetidine etc.
Term " perfluoroalkyl " is meant that all hydrogen atoms are all by the displaced alkyl as defined above of fluorine atom.
For this description, following abbreviation has specified implication:
The Me=methyl
The Et=ethyl
The n-Pr=n-pro-pyl
The i-Pr=isopropyl
The n-Bu=normal-butyl
The i-Bu=isobutyl group
The s-Bu=sec-butyl
The t-Bu=tert-butyl group
The c-Pr=cyclopropyl
The c-Bu=cyclobutyl
The c-Pen=cyclopenta
The c-Hex=cyclohexyl
Term " treatment " not only comprises treatment, and the patient is used for the sign and the symptom of reduction of patient disease or disease, but also comprises the asymptomatic patient is prevented that said disease or disease from beginning or stoping the prophylactic treatment of its process at being used to of carrying out.Term " treatment effective dose " refers to and will cause tissue that research worker, veterinary, internist or other clinicist look for, system, animal or human's biology or the medicine of medicinal response or the quantity of forms of pharmacologically active agents.The risk that this term comprises also that will preventing that research worker, veterinary, internist or other clinicist seek organized, biology or medical events appear in system, animal or human is prevented or the amount of the medicine that reduces.
Pharmaceutically useful salt and the hydrate of the present invention includes described here.Pharmaceutically useful salt not only comprises metal (inorganic) salt but also comprises organic salt; At Remington ' s Pharmaceutical Sciences, the 17th edition, provided its catalogue in the 1418th page (1985).Those skilled in the art are well-known to be, the selection of suitable salt form is based on physics and chemical stability, flowable, hygroscopicity and dissolubility.Just as the skilled person will appreciate, pharmaceutically useful salt comprises salt example hydrochloric acid salt, sulfate, phosphate, diphosphate, hydrobromide and nitrate or organic acid salt such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, mesylate, right-toluene fulfonate or pamoate, Salicylate and the stearate of mineral acid without limitation.Similarly, pharmaceutically useful cation comprises sodium, potassium, calcium, aluminum, lithium and ammonium (the especially ammonium salt that forms with secondary amine) without limitation.Because reason listed above, the preferred salt of the present invention comprises potassium, sodium, calcium and ammonium salt.The crystal form, hydrate and the solvate that also comprise formula I chemical compound in the scope of the present invention.
For the purpose of this description, " pharmaceutically useful hydrate " thus refer to the form of a kind of hydration that The compounds of this invention forms with a part or the crystallization of polymolecular water.
Formula I chemical compound can contain one or more asymmetric centers, and can be therefore as racemic modification and racemic mixture, independent enantiomer, non-enantiomer mixture and diastereomer existence separately.This invention is intended to comprise all such isomeric forms of formula I chemical compound.
Some chemical compound described herein contains olefinic double bond, and except as otherwise noted, is intended to comprise E and Z geometric isomer.
Some chemical compound described herein can have the different sites that is connected with hydrogen, is called tautomer.Such example can be ketone and enol form thereof, is called ketone group-enol tautomer.Formula I chemical compound comprises independent tautomer and composition thereof.
It is right that formula I chemical compound can be separated into the diastereomer of enantiomer by for example following method: from for example fractional crystallization methanol or ethyl acetate or its mixture of suitable solvent.Thus obtained enantiomer is to can for example being separated into independent stereoisomer by the acid of use optical activity as resolving agent by conventional method.
Perhaps, the enantiomer of compound of Formula I can have the pure raw material of optically-active of configuration known or reagent by use and carries out stereospecificity and synthesize and obtain.
The present invention also comprises one or more stereoisomer forms, the formula I chemical compound of pure form or stereoisomer mixture form basically.All such isomers all are included in the scope of the present invention.
Because its S1P 1/ Edg1 agonist activity, The compounds of this invention are the immunomodulators that is used for the treatment of or prevents autoimmunity or chronic inflammatory disease.The compounds of this invention can be used for suppressing immune system in the wherein immunosuppressant situation situation in good order as can be used for bone marrow, organ or transplant rejection, autoimmunity and chronic inflammatory disease, comprises systemic lupus erythematosus, chronic rheumatoid arthritis, type i diabetes, inflammatory bowel, biliary cirrhosis, uveitis, multiple sclerosis, Crohn disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmunity myositis, Wei Genashi granuloma, ichthyosis, Ge Leifusishi oculopathy and asthma.The compounds of this invention also can be used for improving vascular integrity.
Chemical compound of the present invention more specifically can be used for treating or prevents to be selected from following disease or disease: the transplanting of organ or tissue; the graft versus host disease that causes by transplanting; comprise rheumatoid arthritis; systemic lupus erythematosus is in interior autoimmunity syndrome; struma lymphomatosa; multiple sclerosis; myasthenia gravis; type i diabetes; uveitis; posterior uveitis; allergic encephalitis; glomerulonephritis; the metainfective autoimmune disease that comprises rheumatic fever and metainfective glomerulonephritis; inflammatory and hyperplasia dermatoses; psoriasis; atopic dermatitis; contact dermatitis; eczematoid dermatitis; seborrheic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; nodular vasculitis; erythema; eosinophilia on the skin; lupus erythematosus; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; the uveitis relevant with Behcet; keratitis; herpetic keratitis; keratoconus; dystrophia epithelialis corneae (dystrophiaepithelialis corneae); corneal leukoma; ocular pemphigus; Mooren's ulcer; scleritis; Ge Leifusishi oculopathy (Graves ' opthalmopathy); Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergy; the reversibility obstructive airway diseases; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or chronic and refractory asthma; late period asthma and airway hyperreactivity; bronchitis; gastric ulcer; the vascular lesion that causes by ischemic disease and thrombosis; ischemic bowel disease; inflammatory bowel; necrotizing enterocolitis; the small intestinal infringement relevant with thermal burn; celiac disease; proctitis; the eosinophilic gastroenteritis; mastocytosis; Crohn disease; ulcerative colitis; migraine; rhinitis; eczema; interstitial nephritis; goodpasture syndrome; hemolytic uremic syndrome; diabetic nephropathy; the sugar polymyositis; guillain-Barre syndrome; Meniere; polyneuritis; polyneuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's disease; simple property erythroid aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; erythrocyte takes place can not; osteoporosis; sarcoidosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; the vitiligo vulgaris disease; ichthyosis vulgaris; photo-allergy sensitivity; cutaneous T cell lymphoma; arteriosclerosis; atherosclerosis; arteritis syndrome; polyarteritis nodosa; myocardosis; scleroderma; the Wei Genashi granuloma gangraenescens; sjogren's syndrome; obesity; the eosinocyte fascitis; gum; periodontal tissue; the infringement of alveolar bone; substantiaossea dentis; glomerulonephritis; male pattern alopecia or senile alopecia (by preventing alopecia or providing the hair rudiment and/or generation of promotion hair and natural on-off cycles of hair growth); muscular dystrophy; the assorted Reye syndrome of pyoderma and match; addisonian syndrome; in protection; the ischemia-reperfusion damage of the organ that takes place when transplanting or ischemic disease; endotoxin shock; pseudomembranous colitis; the colitis that causes by medicine or radiation; the ischemic acute renal insufficiency; chronic renal insufficiency; by lung-oxygen or drug induced toxinosis; pulmonary carcinoma; emphysema; cataract; arc-welder's disease; retinitis pigmentosa; senile degeneration of macula; the vitreal cicatrization;, cornea highly basic burn; erythema multiforme dermatitis (dermatitis erythema multiforme); linearIgA ballous dermatitis and cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; the disease that causes by environmental pollution; old and feeble; carcinogenesis; cancerometastasis and discharge the altitude sickness that causes by histamine or leukotriene-C4; Behcet; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial hepatectomy; acute severe hepatitis; the necrosis that causes by toxin; viral hepatitis; shock; or anoxia; the B-viral hepatitis; non--A/ is non--hepatitis B; liver cirrhosis; alcoholic cirrhosis; liver failure; fulminant hepatic failure; the liver failure of late onset; " acute-on-chronic " liver failure; the reinforcement of chemotherapy effect; cytomegalovirus infection; HCMV infects; AIDS; cancer; alzheimer disease; wound and chronic bacterial infection.
Chemical compound of the present invention also can be used for treatment or prevention Alzheimer.
The present invention also comprises the toleration that mammalian subject that a kind of prevention or treatment need such prevention or treatment is transplanted organ or tissue or the method for transplant rejection, and it comprises the formula I chemical compound of administering therapeutic effective dose.
Another embodiment of the invention is a kind of immune method that need to suppress the mammalian subject of such inhibition, and described method comprises to this patient uses the formula I chemical compound that can suppress the immune system amount.
Method described here the most specifically comprises a kind of treatment or prevention bone marrow or organ-graft refection's method, and described method comprises that the amount can effectively treat or prevent bone marrow or organ-graft refection is needed the mammalian subject of such treatment or prevention to use formula I chemical compound or its pharmaceutically useful salt or its hydrate.
The compounds of this invention also can be used for treating respiratory disorder or disease, organizes pneumonia as asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, acidophil granuloma, respiratory syncytial virus bronchiolitis, bronchiectasis, idiopathic pulmonary fibrosis, acute lung injury and obstructive bronchiolitis.
In addition, The compounds of this invention still has and surpasses S1P 3The S1P of/Edg3 receptor-selective 1/ Edg1 receptor selective agonists.The Edg1 selective agonist has the advantage that is better than present therapy and has enlarged the treatment window of lymphocyte chelating agen, can tolerate higher dosage and improve its effectiveness as monotherapy thereby the expansion of treatment window is feasible.
The present invention also comprises the pharmaceutical preparation that comprises pharmaceutically suitable carrier and formula I compound or pharmaceutically acceptable salt thereof or hydrate.A kind of embodiment preferred of said preparation is a kind of preparation that wherein also comprises second kind of immunosuppressant.The example of such second kind of immunosuppressant comprises azathioprine, brequinar sodium, deoxyspergualin, mizaribine, mycophenolic acid morpholine ester, cyclosporin, FK-506, rapamycin, FTY720 and ISAtx247 (Isotechnika) without limitation.The present invention also comprises formula I chemical compound and the method that comprises second kind of immunosuppressant co-administered of one or more above-mentioned substances.
Chemical compound of the present invention comprises that its salt and hydrate can be used for treating autoimmune disease, comprises being used to prevent the repulsion of bone marrow graft, external organ graft and/or relevant torment, disease and sufferer.
Can be with making the contacted any method of the intravital site of action of this active compound component and homoiothermic animal that chemical compound of the present invention is carried out administration.For example, its oral administration, topical can be comprised administration and parenteral in percutaneous dosing, ophthalmic administration, cheek administration, intranasal administration, inhalation, intravaginal administration, rectally, the brain pond.Terminology used here " parenteral " refers to and comprises in subcutaneous, intravenous, intramuscular, intra-articular injection or input, the breastbone and endoperitoneal mode of administration.
Can with any obtainable means that make things convenient for of single therapeutic agent or therapeutic agent cooperative programs and medication combined application described chemical compound be carried out administration with any being suitable for.It can still normally be carried out administration with selected pharmaceutical carrier on the basis of selected route of administration and standard pharmaceutical practice by independent administration.
Dosage will depend on receiver's age, health and body weight, the degree of disease, the kind of concurrent treatment if present, required therapeutic frequency and interaction property.The daily dose of active compound component is generally about 0.1-2000 milligram every day.Usually, 1 to 100 milligram of reactive compound using once a day or several times can effectively obtain required result.These dosage are treatment autoimmune disease, the repulsion of the external organ graft of prevention and/or the effective dose of relevant misery, disease and sufferer.
Described active component can be with solid dosage forms or liquid dosage form form by oral administration, described solid dosage forms such as capsule, tablet, lozenge, dragee, granule and powder, described liquid dosage form such as elixir, syrup, Emulsion, dispersion and suspension.Described active component can also be with the form of sterile liquid dosage form such as dispersion, suspension or solution by parenteral.Can be used for other dosage form that said active component carries out administration also is useful on ointment, emulsifiable paste, drop, percutaneous patch or the powder of topical; The ophthalmic solution or suspension form, the i.e. eye drop that are used for ophthalmic administration; Be used to suck or the aerosol spray agent or the powder composition of intranasal administration or be used for rectum or the emulsifiable paste of vagina administration, ointment, spraying or suppository.
Gelatine capsule comprises active component and powder carrier, as lactose, starch, cellulose derivative, magnesium stearate, stearic acid or the like.Can also prepare compressed tablet with similar diluent.Tablet and capsule can be prepared to the slow release product of the lasting release that is used for providing medicine in a few hours.Can compressed tablet sugar coating or peplos clothing be subjected to atmospheric effect to cover any taste beastly with this tablet of protection, perhaps can wrap casing with selectivity disintegrate in gastrointestinal tract it.
The liquid dosage form that is used for oral administration can comprise coloring agent and correctives to increase patient's acceptance.
Generally speaking, water, suitable oil, saline, aqueous dextrose (glucose) and relevant sugar juice and glycol such as propylene glycol or Polyethylene Glycol are the carriers that is applicable to parenteral solution.The solution that is used for parenteral preferably comprises the water soluble salt of active component, suitable stabilizing agent and buffer substance if necessary.Suitable antioxidant is the stabilizing agent that suits for example separately or unite sodium sulfite, sodium sulfite or the ascorbic acid of use.Can also use citric acid with and salt and EDTA sodium.In addition, parenteral solution can also comprise antiseptic, as benzalkonium chloride, methyl hydroxybenzoate or propylparaben and methaform.
At Remington ' s Pharmaceutical Sciences, among the A.Osol (a kind of canonical reference textbook in this area) suitable pharmaceutical carrier is described.
For inhalation, chemical compound of the present invention can be transmitted with aerosol spray form from pressurized package or aerosol apparatus easily.This chemical compound can also be transmitted to have carried out the powder formulated form, and can suck described powder composition under the help that is blown into the powder inhalator device.For suction, preferred transmission system is a kind of suction (MDI) aerosol of dosing, its chemical compound that can be produced accepted way of doing sth I in suitable propellant such as fluorocarbon or hydrocarbon suspension or the form of solution.
For ophthalmic administration, ophthalmic preparation can be used in suitable eye and be prepared with the solution or the suspension that have suitable percentage by weight formula I chemical compound in the substrate, thereby thereby making described chemical compound can contact time enough with ocular surface makes this chemical compound can be penetrated in eye's cornea and the interior zone.
The pharmaceutical dosage form that can be used for The compounds of this invention is carried out administration is as described below:
Capsule
Prepare many units capsule by two parts formula hard gelatin capsule of each standard being filled with 100 milligrams of powdered activated compositions, 150 milligrams of lactose, 50 milligrams of celluloses and 6 milligrams of magnesium stearate.
Perle
Thereby the preparation active component in digestible oil such as Oleum Glycines, Oleum Gossypii semen or olive oil mixture and by displacement pump it is expelled in the gelatin and forms the Perle that comprises 100 milligrams of active component.These capsules are washed and drying.
Tablet
Thereby prepare many tablets with conventional method and make that this dosage unit is 100 milligrams of active component, 0.2 milligram of silica sol, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline Cellulose, 11 milligrams of starch and 98.8 milligrams of lactose.Can use suitable coating absorbs to increase its palatability or to postpone.
Injectable preparation
Stir in the propylene glycol of 10% volume by active component and to prepare a kind of parenteral compositions that is suitable for drug administration by injection 1.5% weight.With water for injection the volume-adjustment of this solution is sterilized to capacity and to it.
Suspension
Prepare a kind of aqueous suspension that is used for oral administration, thereby make per 5 milliliters of suspensions comprise 100 milligrams of active component of cutting apart very carefully, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 Keshan pears alcoholic solution U.S.P. and 0.025 milliliter of vanillin.
When chemical compound of the present invention during, can use identical dosage form usually by administration progressively or with another kind of therapeutic agent coupling.When these medicines with the physical combination form during by administration, can according to merging medicine the compatibility come dosage form and route of administration are selected.Therefore, the term co-administered is understood to include two kinds of activating agents accompany administration or administration in succession, perhaps carries out administration with the form of two kinds of active component fixed dosage compositionss.
Synthetic method
The several method of preparation The compounds of this invention has been described in following reaction scheme and embodiment.Raw material and intermediate are by known method or as shown here making.
Reaction scheme 1 has been described the proper method of (5-(1,2,4- diazole-3-yl) Phenylpyrrolidine-3-yl) acetic acid compound of preparation formula of structure 1-11 of the present invention.With the methoxybenzene 1-1 that suitably replaces with pyroglutamic acid 1-2 in high temperature at trifluoromethanesulfanhydride anhydride (Bull.Korean Chem.Soc.1999,20,1253-1254) or under five phosphorous oxide or the methanesulfonic acid existence handle (Tetrahedron Lett.1989,30,7057-7060), obtain lactams 1-3.The 5-methoxyl group of 1-3 changes into the nitrile of 1-4 and can finish in three sequence of steps: 1) for example in dichloromethane or the dichloroethanes, use strong lewis acid for example TMSI, AlCl at suitable solvent 3, BCl 3Or BBr 3With the 1-3 demethylation, obtain phenol; 2) at suitable solvent for example dichloromethane, dichloroethanes, N-Methyl pyrrolidone or N, in the dinethylformamide, at suitable alkali N for example, N-diisopropylethylamine, triethylamine, pyridine or lutidines exist down, use trifluoromethanesulfanhydride anhydride, 2-(N, N-two (trifluoromethyl sulfonyl) amino)-5-chloropyridine or N-phenyl-two (fluoroform sulfimide) to form trifluoromethayl sulfonic acid ester (being triflate); With 3) in room temperature or the above temperature of room temperature, at suitable solvent for example oxolane, dioxane, N-Methyl pyrrolidone or N, in the dinethylformamide, with zinc cyanide or copper cyanider and adopt for example triphenylphosphine or 1 of suitable part, the palladium catalyst (0) of 1 '-two (diphenylphosphino) ferrocene is handled with this triflate.Realize that in two sequence of steps allylic introducing is to provide 1-5:1) for example Boc, Cbz, Fmoc or trifluoroacetyl group are protected with suitable protecting group (P) with the lactams of 1-4; With 2) with the lactams of gained N-protected with highly basic N for example, N-lithium diisopropylamine, two (trimethyl silyl) potassamide, two (trimethyl silyl) Sodamide .s or sodium hydride are handled, and add the allylic electrophilic reagent then.Can obtain the trans and mixture cis addition product, and these two kinds of stereoisomers can use method known to those skilled in the art for example silica gel chromatography, HPLC or crystallization and easily separate.When adopting allyl iodide and N, during the N-lithium diisopropylamine, can mainly form the trans-addition thing.The cis addition product can be by separating from reactant mixture or using above-mentioned highly basic that trans-addition thing epimerization is easily obtained.The alkene of 1-5 changes into the ester of 1-6 and can realize in two sequence of steps: 1) use method known to those skilled in the art that the olefin oxidation of 1-5 is cracked into carboxylic acid, described method has been summarized in the literature (referring to March, J., " Oxidative Cleavage of Double Bonds and Aromatic Rings ", pp.1181-1183 in Advanced Organic Chemistry, John Wiley ﹠amp; Sons, 1992); With 2) at strong acid H for example 2SO 4Or the HCl existence down, uses (trimethyl silyl) Azimethylene., Azimethylene. or MeOH or EtOH with the gained carboxylic esterification, obtains 1-6.Removing protecting group P can finish according to the chemical property of P.For example, if P is the Boc group, for example trifluoroacetic acid or hydrochloric acid generate lactams 1-7 with the 1-6 hydrolysis then to use strong acid.In room temperature or the above temperature of room temperature, at suitable solvent for example among MeOH or the EtOH, at suitable alkali for example triethylamine, N, N-diisopropylethylamine, sodium carbonate, potassium carbonate or sodium bicarbonate exist down, handle nitrile 1-7 with hydroxy amine hydrochloric acid salt, obtain amidine oxime 1-8, in the presence of suitable alkali and solvent, it is handled with the activating carboxy acid, obtain the N-acyloxy amidine of general formula 1-9.Carboxylic acid in this reaction can be used for the activation of acidylate in the following manner: at solvent for example 1; 2-dichloroethanes, toluene, dimethylbenzene, THF, acetonitrile, N; in dinethylformamide or the N-Methyl pyrrolidone; at suitable alkali (if necessary) for example triethylamine, N; N-diisopropylethylamine or sodium bicarbonate exist down; with reagent N for example; N '-dicyclohexylcarbodiimide (EDC), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide, 1,1 '-carbonyl dimidazoles or two (2-oxo-3- oxazolidinyl) phosphonic chloride activates it.Perhaps, can in the presence of above-mentioned alkali and solvent, use acyl chlorides, anhydride, acylimidazole or pentafluorophenyl group carboxylate that 1-9 is provided.Intermediate 1-9 can use method known to those skilled in the art, and for example silica gel chromatography, HPLC or crystallization separate, and in step subsequently, by in step subsequently, at suitable solvent for example 1,2-dichloroethanes, toluene, dimethylbenzene, THF, acetonitrile, N warmly in dinethylformamide or the N-Methyl pyrrolidone come cyclization/dehydration, to generate 1 of general formula 1-10,2,4- diazole.1-9 is changed into 1-10 can need to add suitable alkali for example pyridine, N ' N-diisopropylethylamine or tetrabutylammonium.It may be more convenient or desirable not separating N-acyloxy amidine 1-9, and 1-8 changes into 1-10 and can be used as continuation method and carry out like this.Preparation 1,2, other method of 4- diazole is potential relevant with the present invention, and is well known by persons skilled in the art, summarize in the literature (referring to Clapp, L.B., " 1; 2,3-and 1,2; 4- diazole ", pp.366-91, ComprehensiveHeterocyclic Chemistry, Volume 6, Potts, K.T., Editor, Pergamon Press, 1984).Final compound 1-11 can be obtained in three steps orders by 1-10: 1) for example in dichloromethane or the dichloroethanes, use Tetrafluoroboric acid trimethyl oxygen , Fumette or dimethyl sulfate that the lactams of 1-10 is changed into imido ether at suitable solvent; 2) at suitable solvent for example in methanol, ethanol or the isopropyl alcohol, in the pH of 4-5 scope (if necessary), for example sodium cyanoborohydride or sodium borohydride reduce imido ether to use appropriate reductant; With 3) basis-CO 2The chemical constitution of A, with carboxyester hydrolysis become carboxylic acid (promptly-CO 2A →-CO 2H).Such representative example includes, but is not limited to: if-A is-CH 3Or-CH 2CH 3,, for example among methanol, ethanol, dioxane or the THF, handle with Lithium hydrate, sodium hydroxide or potassium hydroxide, to generate 1-11 at suitable cosolvent then in room temperature or the temperature more than the room temperature.
Reaction scheme 1
Reaction scheme 2 has been described for example 3 kinds of methods of 2-2,2-4 and 2-6 of preparation amidine oxime intermediate.These intermediate can be in the mode of the intermediate 1-8 that is similar to reaction scheme 1, come to condense to form 1 with carboxylic acid or activating carboxy acid, 2,4- diazole intermediate, the 1-10 in the reaction scheme 1 for example, can carry out suitable functional group's conversion according to being similar to the method for describing in the reaction scheme 1 then, to generate the chemical compound of the general formula 1-11 that describes among the present invention.According to the chemical property of P, removing of the protecting group P of 1-5 can be finished (reaction scheme 2-1) under acidity or alkali condition.For example, if P is the Boc group, for example trifluoroacetic acid or hydrochloric acid generate lactams 2-1 with the 1-5 hydrolysis then to use strong acid.In room temperature or the above temperature of room temperature, at suitable solvent for example among MeOH or the EtOH, at suitable alkali for example triethylamine, N, N-diisopropylethylamine, sodium carbonate, potassium carbonate or sodium bicarbonate exist down, handle lactams 2-1 with hydroxy amine hydrochloric acid salt, obtain amidine oxime 2-2.Can use then to be similar to the combination of describing in the reaction scheme 1 that is used for 1-8 is changed into the proper method of 1-11, amidine oxime 2-2 (and other amidine oxime of listing in this reaction scheme) is changed into chemical compound as described in the present invention.On the other hand, can also in three steps orders, lactams 2-1 be changed into the pyrrolidine of protection: 1) for example in dichloromethane or the dichloroethanes, use Tetrafluoroboric acid trimethyl oxygen , Fumette or dimethyl sulfate that the lactams of 2-1 is changed into imido ether at suitable solvent; 2) at suitable solvent for example in methanol, ethanol or the isopropyl alcohol, in the pH of 4-5 scope (if necessary), for example sodium cyanoborohydride or sodium borohydride reduce imido ether to use appropriate reductant; With 3) with the gained pyrrolidine with for example Boc, Cbz, Fmoc or trifluoroacetyl group protection (reaction scheme 2-2) of suitable protecting group (P ').Then in room temperature or the above temperature of room temperature, at suitable solvent for example among MeOH or the EtOH, at suitable alkali for example triethylamine, N, N-diisopropylethylamine, sodium carbonate, potassium carbonate or sodium bicarbonate exist down, handle pyrrolidine 2-3 with hydroxy amine hydrochloric acid salt, obtain amidine oxime 2-4.Similarly, in four sequence of steps, the lactams 1-6 of N-protected is changed into the pyrrolidine 2-5 (reaction scheme 2-3) of N-protected:, can under alkalescence or acid condition, finish the removing of protecting group P (reaction scheme 2-1) of 1-6 as mentioned above 1) according to the chemical property of P; 2) for example in dichloromethane or the dichloroethanes, use Tetrafluoroboric acid trimethyl oxygen , Fumette or dimethyl sulfate that the gained lactams is changed into imido ether at suitable solvent; 3) at suitable solvent for example in methanol, ethanol or the isopropyl alcohol, in the pH of 4-5 scope (if necessary), for example sodium cyanoborohydride or sodium borohydride reduce imido ether to use appropriate reductant; With 4) with the gained pyrrolidine with for example Boc, Cbz, Fmoc or trifluoroacetyl group protection of suitable protecting group (P ').At last, in room temperature or the above temperature of room temperature, at suitable solvent for example among MeOH or the EtOH, at suitable alkali for example triethylamine, N, N-diisopropylethylamine, sodium carbonate, potassium carbonate or sodium bicarbonate exist down, handle pyrrolidine 2-5 with hydroxy amine hydrochloric acid salt, obtain amidine oxime 2-6.
Reaction scheme 2
Figure A20058003626500361
According to the method for describing among the 1-3 that is similar to reaction scheme 1, reaction scheme 3 has been described two kinds of distinct methods of synthetic 5-aryl-ketopyrrolidine or 6-aryl-piperidones.At first; at suitable solvent for example in dichloromethane or the dichloroethanes; at suitable lewis acid for example in the presence of aluminum chloride, iron chloride, zinc chloride or the boron trifluoride; with the methoxybenzene 1-1 that suitably replaces with succinic anhydrides or glutamic acid acid anhydride 3-1 acidylate; generate keto-carboxylic acid, then more than 0 ℃ or 0 ℃, in suitable acid for example in the presence of Tetrafluoroboric acid, hydrochloric acid or the concentrated sulphuric acid; it is handled with methanol, generate methyl ester 3-2 (reaction scheme 3-1).In room temperature or the above temperature of room temperature, at suitable solvent for example in methanol, ethanol or the isopropyl alcohol, at suitable alkali for example triethylamine, N, N-diisopropylethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate or sodium acetate exist down, 3-2 handles with hydroxy amine hydrochloric acid salt with ketone, generates ketoxime 3-3.At suitable solvent methanol for example, in ethanol or the acetic acid, at Bronsted acid for example in the presence of hydrochloric acid or the acetic acid (if necessary), use for example palladium on carbon of appropriate catalyst, with carbon is the palladium dydroxide of carrier, platinum oxide (IV) or Raney nickel, with ketoxime 3-3 hydrogenation, generate amine, then in room temperature or the above temperature of room temperature, at suitable solvent THF for example, ether, in pyridine or the toluene, with this amine with suitable alkali triethylamine for example, N, the N-diisopropylethylamine, pyridine, lutidines, potassium carbonate or sodium carbonate are handled, and are similar to ketopyrrolidine or the piperidones of 1-3 with generation.Perhaps, can be with phenyl-magnesiumhalide and the 5-ethyoxyl-2-Pyrrolidone (Org.Prep.Proc.Int.1993 that suitably replaces, 25,255-258) or 6-ethyoxyl-2-piperidones (J.Heterocyclic Chem.1970,7,615-622) reaction is to generate ketopyrrolidine or the piperidones that is similar to 1-3 respectively.Grignard reagent 3-4 can use method known to those skilled in the art to make, and summarized in the literature (referring to March, J., " Aliphatic ElectrophilicSubstitution ", pp.622-625 in Advanced Organic Chemistry, John Wiley﹠amp; Sons, 1992, and Knochel, people such as P., " Functionalized Main-GroupOrganometallics for Organic Synthesis " Pure Appl.Chem.2002,74,11-17).R 1To R 4And R 12Be the functional group compatible, and use method known to those skilled in the art can at an easy rate the latter be changed into the amidine oxime to be used for subsequently  diazole synthetic with reaction condition.
Reaction scheme 3
Figure A20058003626500381
Reaction scheme 4 has been described acetic acid functional group is introduced ketopyrrolidine or the intra-annular three kinds of methods of piperidones.At first, in room temperature or the above temperature of room temperature, at suitable solvent dichloromethane for example, dichloroethanes, THF, in ether or the toluene, can be with 5-aryl-ketopyrrolidine of suitably replacing or 6-aryl-piperidones 4-1 with highly basic N for example, the N-lithium diisopropylamine, two (trimethyl silyl) potassamide, two (trimethyl silyl) Sodamide .s or sodium hydride are handled, add 2-alkyl halogen acetates or 2-trifluoro sulfonyloxy alkyl acetate then, wherein alkyl can be a methyl, the ethyl or the tert-butyl group, and halogen can be a chlorine, bromine or iodine obtains 4-2 (reaction scheme 4-1).Lactams 4-2 changes into The compounds of this invention and can use those skilled in the art known and be similar to the method that reaction scheme 1 ester describes and finish.Perhaps, can be in room temperature, at suitable solvent for example in dichloromethane, dichloroethanes, THF, ether or the toluene, ketopyrrolidine or piperidones 4-1 are handled with above-mentioned highly basic, add alkyl chloroformate then, wherein alkyl can be methyl, ethyl or isopropyl, obtains 4-3.Can in three sequence of steps, ketopyrrolidine or piperidones 4-3 be changed into pyrrolidine or piperidines 4-4 (reaction scheme 4-2): 1) for example in dichloromethane or the dichloroethanes, use Tetrafluoroboric acid trimethyl oxygen , Fumette or dimethyl sulfate that the lactams of 4-3 is changed into imido ether at suitable solvent; 2) at suitable solvent for example in methanol, ethanol or the isopropyl alcohol, in the pH of 4-5 scope (if necessary), for example sodium cyanoborohydride or sodium borohydride reduce imido ether to use appropriate reductant; With 3) with the gained pyrrolidine with for example Boc, Cbz, Fmoc or trifluoroacetyl group protection of suitable protecting group (P ').The reduction of the ester of 4-4 can be at low temperatures, and for example in dichloromethane, dichloroethanes, toluene, THF or the ether, for example lithium aluminium hydride, diisobutylaluminium hydride or lithium triethylborohydride are realized to use appropriate reductant at suitable solvent.Can be in two sequence of steps the hydroxyl of 4-5 be changed into cyanide 4-6:1) use method known to those skilled in the art, hydroxyl is changed into suitable leaving group for example methanesulfonates, tosylate, triflate, bromide or iodide; With 2) in room temperature or the above temperature of room temperature,, in dinethylformamide or the acetone, use Cyanogran., potassium cyanide or cyaniding TBuA that the gained leaving group is replaced at suitable solvent for example methyl sulfoxide, N.The hydrolysis of the cyanide group of 4-6 can be at high temperature, for example in methanol, ethanol or the isopropyl alcohol, uses Lithium hydrate, sodium hydroxide or potassium hydroxide aqueous solution to finish at suitable cosolvent.At last, can for example in dichloromethane, dichloroethanes, THF, ether or the toluene, ketopyrrolidine or piperidones 4-1 be handled with above-mentioned highly basic at suitable solvent, add aldehydes or ketones then, add for example hydrochloric acid of suitable Bronsted acid afterwards, obtain 4-8 (reaction scheme 4-3).Use the method for in reaction scheme 1 and reaction scheme 4, describing well known by persons skilled in the art at an easy rate hydroxyl to be changed into carboxylic acid.
Reaction scheme 4
Figure A20058003626500401
At last, reaction scheme 5 has been described two kinds of assorted [2+3] cycloaddition methods, and with preparation 2-aryl-4-pyrrolidine, this pyrrolidine has the functional group that can easily change into acetic acid.Can be in the reaction tube (if necessary) of sealing, at high temperature, at suitable solvent for example in acetonitrile, dichloromethane, dichloroethanes, benzene, toluene or the dimethylbenzene, with 6,6-dimethyl-4,8-two oxa-s-1-methylene spiral shell [2,5] octane 5-1 and the benzaldehyde O-methyloxime 5-2 reaction that suitably replaces, generation ketene acetal 5-3 (J.Org.Chem.1998,63,1694-1703).At suitable solvent for example in THF or the acetonitrile, for example finish the hydrolysis of ketene acetal 5-3 in the presence of acetic acid or the aqueous solution of hydrochloric acid at suitable Bronsted acid.Use method known to those skilled in the art pyrrolidine 5-4 can be changed into The compounds of this invention.On the other hand; can be at high temperature; at suitable solvent for example in THF or the dioxane; adopting suitable part for example in the presence of palladium (0) catalyst of triphenylphosphine or triisopropyl phosphite; N-tosyl imines 5-5 and acetic acid ((trimethyl silyl) methyl) allyl ester 5-6 are reacted (J.Am.Chem.Soc.1993; 115,6636-6645).Can use method known to those skilled in the art that pyrrolidine 5-7 is changed into The compounds of this invention.
Reaction scheme 5
Representative embodiment
The The compounds of this invention that illustrates as described below:
Conventional method
Reaction for moisture or air-sensitive is carried out under nitrogen or argon with anhydrous solvent and reagent.Reaction process is definite by LC-MS or analysis thin layer chromatography (TLC), and thin layer chromatography is with E.Merck pre-coating TLC flat board, silica gel 60F-254, and bed thickness 0.25mm carries out.The concentrated of solution carries out under reduced pressure with Rotary Evaporators.Flash chromatography is to go up at silica gel (32-63mM, 60  apertures) with Biotage Flash Chromatography device (Dyax Corp.) to carry out in the specified size tube that is pre-charged with.Except as otherwise noted, 1H NMR spectrum is at CDCl 3On the 500MHz spectrometer, obtain in the solution.Chemical shift is reported with 1,000,000 umbers.At CD 3In the Cl solution, use tetramethylsilane (TMS) as interior mark, at CD 3In the OD solution, use remaining CH 3OH peak or TMS are as interior mark.Coupling constant (J) is reported with hertz (Hz).Abbreviation: ethyl acetate (EtOAc), ether (ether or Et 2O), triethylamine (TEA), N, N-diisopropylethylamine (DIEA), N, dinethylformamide (DMF), oxolane (THF), trifluoroacetic acid (TFA), saturated aqueous solution (saturated), room temperature (rt), hour (s) (h or hr) and minute (min).High performance liquid chromatography (HPLC) is carried out on ADV731020 100 * 20mm post, and gradient is 10: 90-95: 5 v/vCH 3CN/H 2O+v0.05%TFA 23 minutes, remains on 95: 5 v/v CH 3CN/H 2O+0.05%TFA, 7 minutes; 10mL/ minute, 254nm.
Preparation amidine oxime intermediate
Amidine oxime 1
Trans-5-(4-(amino (oxyimino) methyl) phenyl)-2-oxo-3-methyl pyrrolidineacetate
Steps A: 5-(4-trifyl oxygen base phenyl)-2-Pyrrolidone
DIEA (2.89mL, 16.6mmol) be added to 5-(4-hydroxy phenyl)-2-Pyrrolidone (1.47g, 8.30mmol) and N-phenyl trifluoromethanesulfonate methylsulfonyl imines (4.45g, 12.45mmol) in the solution of 10mLDMF, and with this solution in stirred overnight at room temperature.With this reactant mixture with EtOAc (100mL) washing, and with saline (50mL), H 2O (3 * 50mL) and saline (50mL) washing.Organic layer is separated, use MgSO 4Drying, and concentrate.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+M tube purification, as eluant, obtain this title compound of 2.45g (96%) with EtOAc, be white solid: 1H NMR δ 1.90-1.98 (m, 1H), 2.38-2.51 (m, 2H), 2.57-2.65 (m, 1H), 4.81 (t, J=7.1,1H), 6.92 (br.s, 1H), 7.27-7.30 (m, 2H), 7.38-7.42 (m, 2H).
Step B:5-(4-cyano-phenyl)-2-Pyrrolidone
With 5-(4-trifyl oxygen base phenyl)-2-Pyrrolidone (2.45g; 8.22mmol), tetrakis triphenylphosphine palladium (475mg; 0.41mmol) and zinc cyanide (1.45g, 12.3mmol) solution in 10mLDMF is with nitrogen purging three times, then in 80 ℃ of stirrings.After 3 hours, this chemical compound is cooled to room temperature, with EtOAc (10mL) dilution, and by the filtration of kieselguhr cake.Wash solid with EtOAc, merging filtrate also concentrates.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+M tube purification, with 9: 1 v/v EtOAc/CH 3OH obtains to contain this title compound of 2.68g (100%) of micro-DMF as eluant: 1H NMR (CD 3OD) δ 1.90-1.97 (m, 1H), 2.43-2.51 (m, 2H), 2.60-2.67 (m, 1H), 4.85 (t, J=7.2,1H), 7.41 (d, J=8.8,2H), 7.65 (d, J=8.5,2H).
Step C:N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-Pyrrolidone
4-(dimethylamino) pyridine (50mg, 0.41mmol) be added to above-mentioned nitrile (2.68g, 8.22mmol) and Bis(tert-butoxycarbonyl)oxide (3.59g is 16.4mmol) to 20mL CH 2Cl 2In the interior solution.This mixture in stirring at room, is concentrated then.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+M tube purification, as eluant, obtain this title compound of 1.16g (74%) with 9: 11 v/v EtOAc/ hexanes: 1H NMR δ 1.30 (s, 9H), 1.82-1.89 (m, 1H), 2.48-2.69 (m, 3H), 5.19 (dd, J=4.2,8.3,1H), 7.35 (d, J=8.2,2H), 7.68 (d, J=8.3,2H).
Step D: trans-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-3-(2-acrylic)-2-Pyrrolidone
The solution of diisopropylaminoethyl lithium (2.80mmol) in 10mL THF of preparation just is added drop-wise to N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-Pyrrolidone in-78 ℃, and (763mg is 2.67mmol) in the solution in 10mL THF.In-78 ℃ stir 1 hour after, add allyl iodide (488 μ L, 5.33mmol).This mixture was stirred 1 hour at-78 ℃, use the saturated NH of 5.0mL then 4Cl solution is ended.This mixture is poured into saline (20mL) and CH 2Cl 2In the mixture (20mL), separate water layer and use CH 2Cl 2(3 * 20mL) extractions.Organic layer is merged, use MgSO 4Drying concentrates.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+M tube purification, as eluant, obtain this title compound of 745mg (86%) with 1: 4 v/v EtOAc/ hexane: 1HNMR δ 1.35 (s, 9H), 1.99-2.05 (m, 1H), 2.21-2.29 (m, 1H), 2.63-2.76 (m, 2H), 5.06-5.11 (m, 2H), 5.17-5.20 (m, 1H), 5.68-5.77 (m, 1H), 7.32 (d, J=8.2,2H), 7.67 (d, J=8.4,2H).
Step e: trans-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-oxo-3-pyrrolidine acetic acid
Ruthenic chloride (III) hydrate (3.5mg, 0.02mmol) be added to trans N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-3-(2-acrylic)-2-Pyrrolidone (252mg, 0.77mmol) and sodium metaperiodate (744mg is 3.48mmol) at 2: 2: 3 v/v/v CCl 4/ CH 3CN/H 2In the solution in the mixed solvent of O (14.0mL).With this mixture in stirring at room after 1 hour, then at H 2O (20mL) and CH 2Cl 2Distribute (20mL).Water layer separated and use CH 2Cl 2(3 * 20mL) extractions.Organic layer is merged, use Na 2SO 4Dry and concentrate, obtain crude acid, be colourless serosity, use it for next step and will not be further purified.
Step F: trans-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate
(solution of 2.0M in hexane, 580 μ L 1.16mmol) are added to the benzene/CH of above-mentioned crude acid at 7: 2 v/v (trimethyl silyl) Azimethylene. 3In the solution in the mixed solvent of OH (18mL).After 30 minutes, this reactant mixture is concentrated.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+M tube purification, as eluant, obtain this title compound of 261mg (94% liang of step) with 9: 11 v/v EtOAc/ hexanes, be white solid: 1H NMR δ 1.36 (s, 9H), 2.21 (ddd, J=1.1,8.7,13.0,1H), and 2.29-2.36 (m, 1H), 2.52 (dd, J=8.7,17.2,1H), 2.92 (dd, J=4.2,17.1,1H), and 3.02-3.06 (m, 1H), 3.68 (s, 3H), 5.24 (d, J=8.4,1H), 7.32 (d, J=8.2,2H), 7.68 (d, J=8.5,2H).
Step G: trans-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate
With above-mentioned methyl ester (261mg, 0.73mmol) at 10mL 20%TFA at CH 2Cl 2In solution in stirring at room 1 hour.This mixture is concentrated, and residue is dissolved in CH 2Cl 2(50mL), and use saturated NaHCO 3Solution (10mL * 2) and saline (10mL) washing.With organic layer Na 2SO 4Dry and concentrated.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+S tube purification, as eluant, obtain this title compound of 167mg (89%) with 4: 1 v/v EtOAc/ hexanes, be white solid: 1H NMR δ 2.25-2.31 (m, 1H), 2.42-2.54 (m, 2H), 2.82-2.92 (m, 2H), 3.68 (s, 3H), 4.84 (dd, J=2.4,8.8,1H), 7.07 (s, 1H), 7.40 (d, J=8.2,2H), 7.67 (d, J=8.2,2H).
Step H: trans-5-(4-(amino (oxyimino) methyl) phenyl)-2-oxo-3-methyl pyrrolidineacetate
Hydroxylamine hydrochloride (45mg, 0.65mmol) be added to the gained lactams (167mg, 0.65mmol) and sodium bicarbonate (272mg is 3.24mmol) at 10mL CH 3In the solution in the OH.This mixture was refluxed 5 hours, be cooled to room temperature then.Precipitate is filtered by 0.2 μ filter, and use CH 3OH (100mL) thorough washing.Filtrate is concentrated, obtain required amidine oxime, be white solid, use it for next step and will not be further purified.
Amidine oxime 2
Cis-5-(4-(amino (oxyimino) methyl) phenyl)-2-oxo-3-methyl pyrrolidineacetate
Steps A: cis-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-3-(2-acrylic)-2-Pyrrolidone
The solution of diisopropylaminoethyl lithium (0.75mmol) in 5mL THF of preparation just is added drop-wise to trans N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-3-(2-acrylic)-2-Pyrrolidone in-78 ℃, and (223mg is 0.68mmol) in the solution in 5mL THF.In-78 ℃ stir 1 hour after, by adding the saturated NH of 5.0mL 4Cl solution is with the stopping of reaction.Make mixture be warmed to room temperature, pour saline (20mL) and CH into 2Cl 2In the mixture (20mL).Water layer separated and use CH 2Cl 2(3 * 20mL) extractions.Organic layer is merged, use Na 2SO 4Dry and concentrated.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+S tube purification, as eluant, obtain 103mg (46%) this title compound and 120mg (54%) parent material with 1: 3 v/v EtOAc/ hexane: 1HNMR δ 1.24 (s, 9H), 1.50-1.57 (m, 1H), 2.22-2.28 (m, 1H), 2.56-2.77 (m, 3H), 4.94-5.07 (m, 3H), 5.71-5.78 (m, 1H), 7.36 (d, J=8.2,2H), 7.66 (d, J=8.2,2H).
Step B: cis-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-oxo-3-pyrrolidine acetic acid
Use is similar to the method for describing in amidine oxime 1, the step e, replace trans-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-3-(2-acrylic)-2-Pyrrolidone with cis-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-3-(2-acrylic)-2-Pyrrolidone, make this title compound.This crude acid is used for next step and will not be further purified.
Step C: cis-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate
Use is similar to the method for describing in amidine oxime 1, the step F, replace trans-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-oxo-3-pyrrolidine acetic acid with cis-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-oxo-3-pyrrolidine acetic acid, make this title compound: 1H NMR δ 1.24 (s, 9H), 1.62-1.69 (m, 1H), 2.62 (dd, J=8.1,17.2,1H), 2.69-2.76 (m, 1H), 2.92 (dd, J=3.9,17.4,1H), 2.98-3.04 (m, 1H), 3.69 (s, 3H), 4.98 (dd, J=7.5,9.5,1H), 7.43 (d, J=8.3,2H), 7.67 (d, J=8.4,2H).
Step D: cis-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate
Use is similar to the method for describing among amidine oxime 1, the step G, replaces trans-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate with cis-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate: 1H NMR δ 1.67-1.74 (m, 1H), 2.52 (dd, J=8.6,17.1,1H), 2.80-2.98 (m, 3H), 3.68 (s, 3H), 4.75 (dd, J=6.8,9.3,1H), 6.51 (s, 1H), 7.48 (d, J=8.2,2H), 7.67 (d, J=8.2,2H).
Step e: cis-5-(4-(amino (oxyimino) methyl) phenyl)-2-oxo-3-methyl pyrrolidineacetate
Use is similar to the method for describing among amidine oxime 1, the step H, replaces cis-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate with trans-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate, makes this title compound.Should will not be further purified and use by rough amidine oxime.
Amidine oxime 3
Trans-5-(4-(amino (oxyimino) methyl) phenyl)-2-oxo-3-(2-acrylic)-pyrrolidine
Steps A: trans-5-(4-cyano-phenyl)-2-oxo-3-(2-acrylic)-pyrrolidine
Use is similar to the method for describing among amidine oxime 1, the step G, replace trans-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate with trans-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-oxo-3-(2-acrylic)-pyrrolidine, make this title compound: 1HNMR δ 2.05-2.12 (m, 1H), 2.23-2.29 (m, 1H), 2.38-2.44 (m, 1H), 2.54-2.64 (m, 2H), 4.77 (dd, J=4.3,8.6,1H), 5.08-5.14 (m, 2H), 5.74-5.80 (m, 1H), 6.55 (br.s, 1H), 7.40 (d, J=8.2,2H), 7.66 (d, J=8.3,2H).
Step B: trans-5-(4-(amino (oxyimino) methyl) phenyl)-2-oxo-3-(2-acrylic)-pyrrolidine
Use is similar to the method for describing among amidine oxime 1, the step H, replaces trans-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate with trans-5-(4-cyano-phenyl)-2-oxo-3-(2-acrylic)-pyrrolidine, makes this title compound.Should will not be further purified and use by rough amidine oxime.
Amidine oxime 4
Trans-N-tert-butoxycarbonyl-2-(4-(amino (oxyimino) methyl) phenyl)-4-methyl pyrrolidineacetate
Steps A: trans-2-(4-cyano-phenyl)-2-H-3,4-dihydro-5-methoxyl group-4-methyl pyrrolidineacetate
(196mg, 0.76mmol) (135mg is 0.91mmol) at 10mL CH with Tetrafluoroboric acid trimethyl oxygen  with trans-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate (referring to amidine oxime 1, step e) 2Cl 2In solution in stirred overnight at room temperature.With this mixture saturated NaHCO of 20mL 3Washing, and with water layer CH 2Cl 2(3 * 20mL) extractions.Organic layer is merged, use Na 2SO 4Dry and concentrated, obtain required methoxyl group imines (207mg, 100%), be colourless serosity: 1H NMR δ 2.15-2.21 (m, 1H), 2.33-2.39 (m, 1H), 2.46 (dd, J=9.5,16.2,1H), 2.75 (dd, J=4.7,16.2,1H), and 3.22-3.28 (m, 1H), 3.70 (s, 3H), 3.93 (s, 3H), 5.06 (dd, J=5.3,8.3,1H), 7.36 (d, J=8.2,2H), 7.61 (d, J=8.3,2H).
Step B: trans-2-(4-cyano-phenyl)-4-methyl pyrrolidineacetate
Sodium cyanoborohydride (1.0M in THF, 7.6mL, 7.6mmol) be added to the methoxyl group imines (207mg, 0.76mmol) and a small amount of bromocresol green at CH 3In the solution in the OH (10mL).1, the solution in the 4-dioxane (2.0M) is added in this reactant mixture HCl so that color is kept yellow, and with this reactant mixture in stirring at room 4 hours.Pour saturated NaHCO into 3Solution and CH 2Cl 2In, and water layer further used CH 2Cl 2(3 * 20mL) extractions.Organic layer is merged, use Na 2SO 4Dry and concentrate, obtain rough amine (158mg, 85%), use it for next step and will not be further purified.
Step C: trans-N-tert-butoxycarbonyl-2-(4-cyano-phenyl)-4-methyl pyrrolidineacetate
Bis(tert-butoxycarbonyl)oxide (170mg, 0.78mmol) be added to gained amine (158mg, 0.65mmol) and the 4-dimethylaminopyridine of catalytic amount at CH 2Cl 2(10mL) in Nei the solution.With this mixture in stirring at room 3 hours.This mixture is concentrated.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+S tube purification, as eluant, obtain this title compound of 208mg (93%) with 3: 7 v/v EtOAc/ hexanes: 1H NMR δ 1.20-1.45 (m, 9H), 1.99-2.14 (m, 2H), 2.37-2.63 (m, 3H), 3.17-3.27 (m, 1H), 3.67 (s, 3H), 3.86-3.88 (m, 1H), 4.87-4.89 (m, 1H), 7.28 (d, J=8.2,2H), 7.61 (d, J=8.0,2H).
Step D: trans-N-tert-butoxycarbonyl-2-(4-(amino (oxyimino) methyl) phenyl)-4-methyl pyrrolidineacetate
Use is similar to the method for describing among amidine oxime 1, the step H, replaces trans-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate with trans-N-tert-butoxycarbonyl-2-(4-cyano-phenyl)-4-methyl pyrrolidineacetate, makes this title compound.Should use and will not be further purified by rough amidine oxime.
Amidine oxime 5
Cis-N-tert-butoxycarbonyl-2-(4-(amino (oxyimino) methyl) phenyl)-4-methyl pyrrolidineacetate
Steps A: cis-2-(4-cyano-phenyl)-2-H-3,4-dihydro-5-methoxyl group-4-methyl pyrrolidineacetate
Use is similar to the method for describing in amidine oxime 4, the steps A, with cis-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate (referring to amidine oxime 2, step C) replace trans-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate, make this title compound: 1H NMR δ 1.51-1.58 (m, and 1H) 2.41 (dd, J=8.8,16.6,1H), 2.79 (dd, J=4.5,16.6,1H), 2.83-2.90 (m, 1H), and 3.27-3.34 (m, 1H), 3.68 (s, 3H), 3.93 (s, 3H), 4.88 (t, J=8.2,1H), 7.44 (d, J=8.2,2H), 7.62 (d, J=8.3,2H).
Step B: cis-2-(4-cyano-phenyl)-4-methyl pyrrolidineacetate
Use is similar to the method for describing among amidine oxime 4, the step B, with cis-2-(4-cyano-phenyl)-2-H-3,4-dihydro-5-methoxyl group-4-methyl pyrrolidineacetate replace methyl trans-2-(4-cyano-phenyl)-2-H-3,4-dihydro-5-methoxyl group-4-methyl pyrrolidineacetate makes this title compound.
Step C: cis-N-tert-butoxycarbonyl-2-(4-cyano-phenyl)-4-methyl pyrrolidineacetate
Use is similar to the method for describing among amidine oxime 4, the step C, with cis-2-(4-cyano-phenyl)-4-methyl pyrrolidineacetate replace methyl trans-2-(4-cyano-phenyl)-4-methyl pyrrolidineacetate, make this title compound: 1H NMR δ 1.12-1.51 (m, 10H), 2.35-2.64 (m, 4H), 3.15 (t, J=9.9,1H), 3.68 (s, 3H), 4.02-4.08 (m, 1H), 4.72-4.81 (m, 1H), 7.30 (d, J=8.1,2H), 7.60 (d, J=8.2,2H).
Step D: trans-N-tert-butoxycarbonyl-2-(4-(amino (oxyimino) methyl) phenyl)-4-methyl pyrrolidineacetate
Use is similar to the method for describing among amidine oxime 1, the step H, with cis-N-tert-butoxycarbonyl-2-(4-cyano-phenyl)-4-methyl pyrrolidineacetate replace methyl trans-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate, make this title compound.Should use and will not be further purified by rough amidine oxime.
Amidine oxime 6
Trans-N-tert-butoxycarbonyl-2-(4-(amino (oxyimino) methyl) phenyl)-4-(2-acrylic)-pyrrolidine
Steps A: trans-2-(4-cyano-phenyl)-2-H-3,4-dihydro-5-methoxyl group-4-(2-acrylic)-pyrrolidine
Use is similar to the method for describing in amidine oxime 4, the steps A, with trans-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-3-(2-acrylic)-2-Pyrrolidone (referring to amidine oxime 1, step C) replaces trans-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate, make this title compound.This raw product is used for next step and will not be further purified.
Step B: trans-2-(4-cyano-phenyl)-4-(2-acrylic)-pyrrolidine
Use is similar to the method for describing among amidine oxime 4, the step B, with trans-2-(4-cyano-phenyl)-2-H-3,4-dihydro-5-methoxyl group-4-(2-acrylic)-pyrrolidine replaces trans-2-(4-cyano-phenyl)-2-H-3,4-dihydro-5-methoxyl group-4-methyl pyrrolidineacetate makes this title compound.
Step C: trans-N-tert-butoxycarbonyl-2-(4-cyano-phenyl)-4-(2-acrylic)-pyrrolidine
Use is similar to the method for describing among amidine oxime 4, the step C, replaces trans-2-(4-cyano-phenyl)-4-methyl pyrrolidineacetate with trans-2-(4-cyano-phenyl)-4-(2-acrylic)-pyrrolidine, makes this title compound: 1H NMR δ 1.20-1.46 (m, 9H), 1.89-2.28 (m, 5H), 3.14-3.27 (m, 1H), 3.71-3.81 (m, 1H), 5.00-5.07 (m, 3H), 5.68-5.77 (m, 1H), 7.27 (d, J=8.2,2H), 7.60 (d, J=8.0,2H).
Step D: trans-N-tert-butoxycarbonyl-2-(4-(amino (oxyimino) methyl) phenyl)-4-(2-acrylic)-pyrrolidine
Use is similar to the method for describing among amidine oxime 1, the step H, replace trans-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate with trans-N-tert-butoxycarbonyl-2-(4-cyano-phenyl)-4-(2-acrylic)-pyrrolidine, make this title compound.Should use and will not be further purified by rough amidine oxime.
Amidine oxime 7
Trans-5-(4-(amino (oxyimino) methyl)-3-methyl-phenyl)-2-oxo-3-(2-acrylic)-pyrrolidine
Steps A: 5-(4-methoxyl group-3-methyl-phenyl)-2-Pyrrolidone
2-Pyrrolidone-5-formic acid (2.0g, 15.5mmol) and 2-methylbenzene methyl ether (2.1mL 17.0mmol) is added in the mixture of methanesulfonic acid of 1.0g (3.52mmol) five phosphorous oxide and 6.7mL.This mixture in 100 ℃ of heating 2 hours, is cooled to room temperature, and pours H into 2O and CH 2Cl 2Mixture in.Water layer is separated, and use CH 2Cl 2(3 * 20mL) extractions.Organic layer is merged, use saturated NaHCO 3Solution washing is used MgSO 4Drying concentrates.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+M tube purification, as eluant, obtain this title compound of 1.78g (56%) with 4: 1 v/v EtOAc/ hexanes: 1H NMR δ 1.88-1.97 (m, 1H), 2.21 (s, 3H), 2.35-2.54 (m, 3H), 3.81 (s, 3H), 4.66 (t, J=7.1,1H), 6.53 (br.s, 1H), 6.79 (d, J=8.6,1H), 7.05-7.09 (m, 2H).
Step B:N-tert-butoxycarbonyl-5-(4-methoxyl group-3-methyl-phenyl)-2-Pyrrolidone
Use is similar to the method for describing among amidine oxime 1, the step C, replaces 5-(4-cyano-phenyl)-2-Pyrrolidone with 5-(4-methoxyl group-3-methyl-phenyl)-2-Pyrrolidone, makes this title compound: 1H NMR δ 1.29 (s, 9H), 1.84-1.90 (m, 1H), 2.20 (s, 3H), 2.39-2.53 (m, 2H), 2.64-2.71 (m, 1H), 3.82 (s, 3H), 5.07 (dd, J=3.6,8.3,1H), 6.78 (d, J=8.3,1H), 6.98-7.00 (m, 2H).
Step C: trans-N-tert-butoxycarbonyl-5-(4-methoxyl group-3-methyl-phenyl)-3-(2-acrylic)-2-Pyrrolidone
Use is similar to the method for describing among amidine oxime 1, the step D, replace trans N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-3-(2-acrylic)-2-Pyrrolidone with N-tert-butoxycarbonyl-5-(4-methoxyl group-3-methyl-phenyl)-2-Pyrrolidone, make this title compound: 1H NMR δ 1.34 (s, 9H), 2.00-2.04 (m, 1H), 2.12-2.24 (m, 5H), 2.63-2.68 (m, 1H), 2.74-2.81 (m, 1H), 3.82 (s, 3H), 5.03-5.10 (m, 3H), 5.69-5.77 (m, 1H), 6.76 (d, J=8.3,1H), 6.94-6.97 (m, 2H).
Step D: trans-5-(4-methoxyl group-3-methyl-phenyl)-3-(2-acrylic)-2-Pyrrolidone
Use is similar to the method for describing in amidine oxime 1, the step e, replace trans-N-tert-butoxycarbonyl-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate with trans-N-tert-butoxycarbonyl-5-(4-methoxyl group-3-methyl-phenyl)-3-(2-acrylic)-2-Pyrrolidone, make this title compound: 1H NMR δ 2.07-2.13 (m, 1H), 2.21 (s, 3H), 2.22-2.33 (m, 2H), and 2.55-2.60 (m, 1H), 2.62-2.66 (m, 1H), 3.82 (s, 3H), 4.61-4.63 (m, 1H), and 5.06-5.14 (m, 2H), 5.77-5.82 (m, 1H), 5.99 (br.s, 1H), 6.78 (d, J=8.0,1H), 7.03-7.06 (m, 2H).
Step e: trans-5-(4-hydroxy-3-methyl-phenyl)-3-(2-acrylic)-2-Pyrrolidone
(10.1mL, 1.0M is at CH Boron tribromide 2Cl 2In solution, (1.13g is 4.61mmol) at 10.0mL CH 10.1mmol) to be added drop-wise to trans-5-(4-methoxyl group-3-methyl-phenyl)-3-(2-acrylic)-2-Pyrrolidone in-78 ℃ 2Cl 2Solution in.This mixture in-78 ℃ of stirrings 30 minutes, was stirred 1 hour in 0 ℃ then.By adding 20mL H 2O is with the stopping of reaction.This mixture pour into ether and EtOAc mixture (1: 1,50.0mL) in, and with 2.0NNaOH (3 * 30mL) extraction.Water layer is merged, use 5.0N HCl acidify, and (3 * 50mL) extract with EtOAc.Organic layer is merged, use MgSO 4Drying concentrates, and obtains this rough title compound of 940mg (88%), is filbert solid, uses it for next step and will not be further purified.
Step F: trans-5-(4-trifyl oxygen base-3-methyl-phenyl)-3-(2-acrylic)-2-Pyrrolidone
Use is similar to the method for describing in amidine oxime 1, the steps A, replaces 5-(4-hydroxy phenyl)-2-Pyrrolidone with trans-5-(4-hydroxy-3-methyl-phenyl)-3-(2-acrylic)-2-Pyrrolidone, makes this title compound: 1H NMR δ 2.08-2.29 (m, 1H), 2.23-2.29 (m, 1H), 2.34-2.40 (m, 4H), 2.55-2.66 (m, 2H), 4.68-4.71 (m, 1H), 5.08-5.15 (m, 2H), 5.75-5.83 (m, 1H), 6.33 (br.s, 1H), 7.16 (dd, J=2.3,8.5,1H), 7.21-7.24 (m, 2H).
Step G: trans-5-(4-cyano group-3-methyl-phenyl)-3-(2-acrylic)-2-Pyrrolidone
Use is similar to the method for amidine oxime 1, step B description; replace 5-(4-trifyl oxygen base phenyl)-2-Pyrrolidone with trans-5-(4-trifyl oxygen base-3-methyl-phenyl)-3-(2-acrylic)-2-Pyrrolidone, make this title compound: 1H NMR δ 2.06-2.11 (m, 1H), 2.23-2.29 (m, 1H), 2.36-2.42 (m, 1H), 2.55-2.64 (m, 5H), 4.71-4.73 (m, 1H), 5.08-5.14 (m, 2H), 5.74-5.80 (m, 1H), 6.41 (br.s, 1H), 7.18 (d, J=8.0,1H), 7.23 (br.s, 1H), 7.59 (d, J=7.8,1H).
Step H: trans-5-(4-(amino (oxyimino) methyl)-3-methyl-phenyl)-2-oxo-3-(2-acrylic)-pyrrolidine
Use is similar to the method for describing among amidine oxime 1, the step H, replaces trans-5-(4-cyano-phenyl)-2-oxo-3-methyl pyrrolidineacetate with trans-5-(4-cyano group-3-methyl-phenyl)-3-(2-acrylic)-2-Pyrrolidone, makes this title compound.Should use and will not be further purified by rough amidine oxime.
Preparation carboxylic acid intermediate
Carboxylic acid 1
4-(4-fluorophenyl)-5-(trifluoromethyl) thiophene-2-carboxylic acid
Steps A: (E/Z)-(2-(4-fluorophenyl)-3-chloro-4,4,4-three fluoro-2-butyraldehyde
(6.8mL 74mmol) is added among the 25mL DMF phosphoryl chloride phosphorus oxychloride in 0 ℃.The gained mixture is warmed to room temperature and stirred 1 hour.Add 1,1,1-trifluoromethyl-3-(4-fluorophenyl)-2-acetone (5.1g, the 24.8mmol) solution in 10mL DMF, and the gained mixture stirred 20 hours at 70 ℃.Reactant mixture is cooled to room temperature, is poured on 100g on ice, and add sodium acetate (6.0g).This mixture in stirring at room 1 hour, is used ether (3 * 100mL) extractions then.Organic layer is merged, use MgSO 4Drying concentrates.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+M tube purification, as eluant, obtain this title compound of 4.0g (64%) with 1: 19 v/v EtOAc/ hexane.
Step B:(4-(4-fluorophenyl)-5-trifluoromethyl) thiophene-2-carboxylic acid ethyl ester
To ethyl thioglycolate (2.1mL, 19.1mmol) and sodium hydride (482mg, 19.1mmol) in the suspension of 20mL THF in 0 ℃ of adding (E/Z)-(2-(4-fluorophenyl)-3-chloro-4,4,4-three fluoro-2-butyraldehyde (4.0g, 15.9mmol).After stirred overnight at room temperature, with the saturated NH of 50mL 4Cl solution stopped reaction.This mixture is distributed between 250mL ether and 100mL water.Organic layer is separated, use Na 2SO 4Dry and concentrated.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+M tube purification, as eluant, obtain this title compound of 4.4g (86%) with 1: 19 v/v EtOAc/ hexane: 1H NMR δ 1.39 (t, J=7.1,3H), 4.39 (q, J=7.2,2H), 7.12 (t, J=8.7,2H), 7.39 (dd, J=5.3,8.5,2H), 7.70 (d, J=1.4,1H).
Step C:4-(4-fluorophenyl)-5-(trifluoromethyl) thiophene-2-carboxylic acid
To (4-(4-fluorophenyl)-5-trifluoromethyl) thiophene-2-methyl acetate (948mg, 3.0mmol) add in the solution in 10mL EtOH sodium hydroxide (358mg, 8.9mmol).Stir after 3 hours, remove and to desolvate, and with the rare HCl of residue (100mL, pH=3) and 1: 1 v/v EtOAc: distribution between the mixture of ether (200mL).Ether (2 * 50mL) extractions are also further used in the water layer separation.Organic layer is merged, use Na 2SO 4Dry and concentrated, obtain this title compound: 1HNMR δ 7.14 (t, J=8.5,2H), 7.39 (dd, J=5.3,8.5,2H), 7.70 (d, J=1.4,1H), 10.6 (br.s, 1H).
Carboxylic acid 2
3-fluoro-4-isobutyl-benzene formic acid
Steps A: 3-fluoro-4-isobutyl-benzene methyl formate
To 4-bromo-3-fluorophenyl carbamate (322mg, 1.38mmol) and the solution of isobutyl group bromination zinc (4.1mL, 0.5M in THF) in 10mL THF in add two (three-tert-butyl group phosphine) palladiums (0) (14mg, 0.03mmol).With nitrogen purging three times of this mixture, then in stirred overnight at room temperature.By adding 5.0mL 1.0N HCl solution, and use Et with this stopping of reaction 2O (3 * 20mL) extractions.Organic layer is merged, use the salt water washing, use MgSO 4Drying concentrates.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage40+S tube purification, as eluant, obtain this title compound of 243mg (84%) with 1: 99 v/v EtOAc/ hexane: 1H NMR δ 0.92 (d, J=6.6,6H), 1.93 (m, 1H), 2.56 (d, J=6.1,2H), 3.91 (s, 3H), 7.21 (t, J=7.6,1H), 7.67 (dd, J=1.5,10.2,1H), 7.74 (dd, J=1.6,7.8,1H).
Step B:3-fluoro-4-isobutyl-benzene formic acid
To 3-fluoro-4-isobutyl-benzene methyl formate (243mg, 1.16mmol) in the solution in 10mL EtOH, add sodium hydroxide (2.3mL, 5.0N).This mixture in stirring at room 1 hour, is concentrated then.With this mixture at rare HCl (10mL) and Et 2Distribute between the O (10mL).Et is also further used in the water layer separation 2O (2 * 10mL) extractions.And the organic layer merging, use the MgSO4 drying, concentrate, obtain this title compound of 212mg (93%): 1H NMR δ 0.93 (d, J=6.6,6H), 1.95 (m, 1H), 2.58 (d, J=7.4,2H), 7.26 (m, 1H), 7.74 (dd, J=1.4,10.1,1H), 7.82 (dd, J=1.5,7.9,1H), 11.2 (br.s, 1H).
Carboxylic acid 3
3-fluoro-4-(3-methyl butyl) benzoic acid
Use is similar to relevant carboxylic acid 2 described methods, replaces isobutyl group bromination zinc with 3-methyl butyl zinc bromide in steps A, makes this title compound: 1H NMR δ 0.95 (d, J=6.4,6H), 1.51 (m, 2H), 1.52 (m, 1H), 2.70 (t, J=8.0,2H), 7.30 (t, J=7.6,1H), 7.72 (dd, J=1.3,10.2,1H), 7.82 (dd, J=1.4,7.8,1H).
Carboxylic acid 4
4-((R)-3,3-difluoro cyclopenta) benzoic acid
Steps A: (3R)-3-(4-bromophenyl) Ketocyclopentane
Under nitrogen to 7.2g (35.8mmol) 4-bromophenyl boric acid, 186mg (0.72mmol) acetyl group acetic acid two (ethylidene) rhodium (I) and 446mg (0.71mmol) (R)-2; 2 '-two (diphenylphosphino)-1,1 '-dinaphthalene (BINAP) is at 60mL dioxane and 6mL H 2In the mixture among the O, add 1.0mL (11.9mmol) 2-cyclopentenes-1-ketone.Reflux after 5.5 hours, should react concentrated.With residue at 300mL EtOAc and 300mL 1N NaHCO 3Between distribute.After being separated, organic layer with the water washing of 300mL salt, is used Na 2SO 4Dry and concentrated.Residue is lived in to carry out purification at 40M Biotage, as eluant, obtains this title compound of 1.90g, be white solid with 9: 1 v/v hexane/EtOAc: 1H NMR δ 1.97 (m, 1H), 2.29-2.37 (m, 2H), 2.43-2.52 (m, 2H), 2.69 (m, 1H), 3.40 (m, 1H), 7.16 (d, J=8.5,2H), 7.49 (d, J=8.5,2H).
Step B:(R)-and 3-(4-bromophenyl)-1,1-difluoro Pentamethylene.
In 0 ℃ 2.1mL (11.4mmol) [two (2-methoxy ethyl) amino] sulfur trifluoride and 0.10mL (0.7mmol) three being fluoridized the solution of ether compound in 7mL toluene placed 1.3 hours under stirring every now and then.Add 1.9g (7.9mmol) (R)-solution of 3-(4-bromophenyl) Ketocyclopentane (deriving from steps A) in 13mL toluene.This is reflected at 55 ℃ stirred 2 days.After the cooling, this mixture is added to 250mL 2N NaOH and 250mL Et in 0 ℃ 2Among the O.Stir after 30 minutes, being separated.With organic layer 250mL 1N NaOH and 250mL H 2MgSO is used in the O washing 4Dry and concentrated.Residue is carried out purification on 40M Biotage post, with 49: 1 v/v hexane/Et 2O obtains this title compound of 1.47g as eluant: 1H NMR δ 1.85 (m, 1H), 2.09-2.26 (m, 3H), 2.35 (m, 1H), 2.56 (m, 1H), 3.30 (m, 1H), 7.13 (d, J=8.3,2H), 7.46 (d, J=8.3,2H).
Step C:4-((R)-3,3-difluoro cyclopenta) benzoic acid
With 1.0g (3.8mmol) (R)-3-(4-bromophenyl)-1, the solution of 1-difluoro Pentamethylene. (deriving from step B) in 15mL THF in-78 ℃ with the mixture process of 1.6mL (4.0mmol) 2.5M Bu Li in hexane.Stir after 15 minutes, this reaction is added to dry ice at 200mL Et 2In the suspension among the O.Make this mixture be warmed to room temperature.This reactant mixture is extracted with 100mL 1NNaOH.After being separated, water layer is acidified to pH 1-2 with dense HCl.With water with 3 * 100mL CH 2Cl 2Extraction.Dry and concentrated the organic facies that merges, obtain this title compound of 0.67g: 1H NMR (CD 3OD) δ 1.87 (m, 1H), 2.13-2.37 (m, 4H), 2.54 (m, 1H), 3.41 (m, 1H), 7.39 (d, J=8.2,2H), 7.97 (d, J=8.2,2H).
Carboxylic acid 5
4-((S)-3,3-difluoro cyclopenta) benzoic acid
Use is similar to relevant carboxylic acid 4 described methods, uses (S)-2 in steps A, 2 '-two (diphenylphosphino)-1, and 1 ' dinaphthalene (BINAP) replaces (R)-2,2 '-two (diphenylphosphino)-1,1 ' dinaphthalene (BINAP): 1H NMR (CD 3OD) δ 1.87 (m, 1H), 2.13-2.37 (m, 4H), 2.54 (m, 1H), 3.41 (m, 1H), 7.39 (d, J=8.2,2H), 7.97 (d, J=8.2,2H).
Carboxylic acid 6
4-((R)-3,3-difluoro cyclohexyl) benzoic acid
Use is similar to relevant carboxylic acid 4 described methods, replaces 2-cyclopentenes-1-ketone with 2-cyclohexene-1-ketone in steps A, makes this title compound: 1H NMR δ 1.47 (m, 1H), 1.66-1.96 (m, 5H), 2.19 (m, 1H), 2.31 (m, 1H), 2.96 (m, 1H), 7.32 (d, J=8.3,2H), 8.07 (d, J=8.2,2H).
Carboxylic acid 7
4-((S)-3,3-difluoro cyclohexyl) benzoic acid
Use is similar to relevant carboxylic acid 6 described methods, and with (S)-2,2 '-two (diphenylphosphino)-1,1 ' dinaphthalene (BINAP) replaces (R)-2,2 '-two (diphenylphosphino)-1, and 1 ' dinaphthalene (BINAP) makes this title compound: 1H NMR δ 1.47 (m, 1H), 1.66-1.96 (m, 5H), 2.19 (m, 1H), 2.31 (m, 1H), 2.96 (m, 1H), 7.32 (d, J=8.3,2H), 8.07 (d, J=8.2,2H).
Carboxylic acid 8
4-((1R, 3R)-3-fluorine cyclopenta) benzoic acid
Steps A: (3S)-3-(4-bromophenyl) cyclopentanol
To (3R)-3-(4-bromophenyl) Ketocyclopentane (1.14g, 4.77mmol, carboxylic acid 4, steps A) at 10mL CH 2Cl 2(7.2mL, 1.0M is at CH to add diisobutyl aluminium hydrides in-78 ℃ in the interior solution 2Cl 2In solution).This mixture was stirred 1 hour at-78 ℃, add the saturated Rochelle's salt solution of 5.0mL then.Pour into this mixture in rare HCl solution and use CH 2Cl 2(3 * 10mL) extractions.Organic layer is merged, use saturated NaHCO 3With the salt water washing.With organic layer MgSO 4Dry and concentrated, obtain this title compound of 1.16g (100%), be the mixture of diastereomers of 1: 1 ratio, it can not separate with chromatography.
Step B: acetic acid (1R, 3R)-3-(4-bromophenyl) cyclopentyl ester and (1S, 3R)-3-(4-bromophenyl) cyclopentanol
With (3S)-3-(4-bromophenyl) cyclopentanol (1.01g, 4.19mmol) and Porcine PancreasLipase (Sigma) suspension in 1: 1 v/v vinyl acetate/hexane of 20.0mL is in stirred overnight at room temperature for PPL, 1.0g.Enzyme filtered by the kieselguhr cake and with EtOAc and hexane wash.Filtrate is concentrated.At the enterprising circumstances in which people get things ready for a trip of Biotage 40+M tube spectrum purification, with 1: 19 v/v EtOAc/ hexane as eluant, acquisition 536mg (45%) acetic acid (1R, 3R)-3-(4-bromophenyl) cyclopentyl ester: 1H NMR δ 1.59 (m, 1H), 1.77-1.89 (m, 2H), 2.05 (s, 3H), 2.12-2.29 (m, 3H), 3.25 (m, 1H), 5.30 (m, 1H), 7.09 (d, J=8.2,2H), 7.41 (d, J=8.3,2H), and with 1: 3 v/v EtOAc/ hexane as eluant, obtain 503mg (50%) (1S, 3R)-3-(4-bromophenyl) cyclopentanol: 1H NMR δ 1.61 (m, 2H), 1.77-1.94 (m, 3H), 2.04 (m, 1H), 2.45 (m, 1H), 3.01 (m, 1H), 4.45 (m, 1H), 7.16 (d, J=8.3,2H), 7.40 (d, J=8.5,2H).
Step C:1-bromo-4-((1R, 3R)-3-fluorine cyclopenta) benzene
To (1S, 3R)-(503mg is 2.09mmol) at 10mL CH for 3-(4-bromophenyl) cyclopentanol 2Cl 2In solution in-78 ℃ of addings (two (2-methoxy ethyl) amino) sulfur trifluoride (Deoxo-Fluor, 462 μ L, 2.50mmol).Make this mixture be warmed to ambient temperature overnight gradually, pour saturated NaHCO then into 3In the solution (20mL).With water layer CH 2Cl 2(3 * 20mL) extractions.Organic layer is dry and concentrated with MgSO4.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+S tube purification, as eluant, obtain this title compound of 383mg (76%) with hexane: 1H NMR δ 1.53-1.78 (m, 2H), 1.95-2.39 (m, 4H), 3.35 (m, 1H), 5.19-5.32 (m, 1H), 7.09 (d, J=8.5,2H), 7.40 (d, J=8.2,2H).
Step D:4-((1R, 3R)-3-fluorine cyclopenta) benzoic acid
Use is similar to relevant carboxylic acid 4 described methods, usefulness 1-bromo-4-in step D ((1R, 3R)-3-fluorine cyclopenta) benzene replacement 1-bromo-4-((1R)-3,3-difluoro cyclopenta) benzene, make this title compound: 1H NMR δ 1.65-1.87 (m, 2H), 1.99-2.46 (m, 4H), 3.47 (m, 1H), 5.23-5.36 (m, 1H), 7.33 (d, J=8.2,2H), 8.05 (d, J=8.2,2H).
Carboxylic acid 9
4-((1R, 3S)-3-fluorine cyclopenta) benzoic acid
Steps A: (1R, 3R)-3-(4-bromophenyl) cyclopentanol
To acetic acid (1R, 3R)-3-(4-bromophenyl) cyclopentyl ester (carboxylic acid 8, step B, 536mg, 1.9mmol) in the solution in 5.0mL EtOH, add sodium hydroxide (1.9mL, 5.0N).In stirring at room 30 minutes, remove and desolvate, and with residue at saturated NaHCO 3Solution (50mL) and CH 2Cl 2Distribute (50mL).Water layer separated and use CH 2Cl 2(2 * 50mL) extractions.Organic layer is merged, use MgSO 4Drying concentrates.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+M tube purification, as eluant, obtain this title compound of 445mg (97%) with 7: 3 v/v hexane/EtOAc: 1H NMR δ 1.49 (br.s, 1H), 1.56-1.81 (m, 2H), 2.05-2.27 (m, 4H), 3.35 (m, 1H), 4.52 (m, 1H), 7.09 (d, J=8.2,2H), 7.40 (d, J=8.3,2H).
Step B:4-((1R, 3S)-3-fluorine cyclopenta) benzoic acid
Use is similar to relevant carboxylic acid 8 described methods, in step C, use (1R, 3R)-replacement of 3-(4-bromophenyl) cyclopentanol (1S, 3R)-3-(4-bromophenyl) cyclopentanol, make this title compound.
Carboxylic acid 10
3-fluoro-4-cyclopenta benzoic acid
With 0.45g (1.45mmol) 3-fluoro-4-bromobenzoic acid benzyl ester (0.45g, 1.45mmol) solution usefulness～5mg two (tri-butyl phosphine) palladium (0) in the solution of 4.4mL 0.5M brominated amyl group zinc in THF handles, and with the gained mixture in stirring at room 24 hours.With this reactant mixture directly is to carry out purification on Biotage 40S tube, with 1: 1 hexane/EtOAc as eluant.With the gained solid (0.27g, 0.91mmol) and the mixture of 10%Pd/C in 5mL MeOH at 1atm H 2Under stirred 3 hours.Should react and filter and concentrate.By HPLC B purification, obtain this title compound: 1H NMR δ 1.58-1.90 (m, 6H), 2.05-2.14 (m, 2H), 3.30 (m, 1H), 7.36 (t, J=7.7,1H), 7.72 (dd, J=1.6,10.5,1H), 7.83 (dd, J=1.6,8.0,1H).
Carboxylic acid 11
2-fluoro-4-cyclopenta benzoic acid
Use is similar to relevant carboxylic acid 10 described methods, replaces benzyl 3-fluoro-4-bromobenzoic acid benzyl ester with 2-fluoro-4-bromobenzoic acid benzyl ester: 1H NMR δ 1.57-1.85 (m, 6H), 2.07-2.13 (m, 2H), 3.05 (m, 1H), 7.03 (dd, J=1.1,12.4,1H), 7.10 (dd, J=1.4,8.2,1H), 7.94 (t, J=8.0,1H).
Carboxylic acid 12
3-trifluoromethyl-4-(((1S)-1-methyl-propyl) oxygen base) benzoic acid
Steps A: 3-trifluoromethyl-4-(2-(S)-butoxy) benzonitrile
With 1.1g (5.9mmol) 4-fluoro-3-trifluoromethyl benzonitrile and 485mg (6.5mmol) (S)-(+)-solution of 2-butanols in 10mL THF handles with 235mg (5.9mmol) sodium hydride in-10 ℃.The gained mixture was stirred 2 hours under cool condition, use 10mL H then 2The O stopped reaction.Solution Et with this stopped reaction 2The O extraction, dry and concentrated with MgSO4.At the enterprising circumstances in which people get things ready for a trip spectrometry of Biotage 40M tube purification, as eluant, obtain this title compound of 550mg with 4: 1 v/v hexane/ethyl acetate: 1H NMR δ 0.99 (t, J=7.6,3H), 1.35 (d, J=6.2,3H), 1.58-1.83 (m, 2H), 4.51 (septet, 1H), 7.04 (d, J=8.7,1H), 7.75 (d, J=8.7,1H), 7.85 (s, 1H).
Step B:3-trifluoromethyl-4-(2-(S)-butoxy) benzoic acid
The solution of 550mg (2.2mmol) 3-trifluoromethyl-4-(2-(S)-methyl propoxyl group) benzonitrile (deriving from steps A) in 5mL ethanol is handled with 1.5mL 5.0N NaOH, and be heated to 80 ℃ 3 hours.Should react concentrated, and handle with 2N HCl, with 30mL EtOAc extraction, drying also concentrates, and obtains this title compound of 600mg: 1H NMR δ 0.99 (t, J=7.3,3H), 1.43 (d, J=5.9,3H), 1.73-1.83 (m, 2H), 4.54 (septet, 1H), 7.02 (d, J=8.9,1H), 8.21 (d, J=8.9,1H), 8.32 (s, 1H).
Carboxylic acid 13
3-chloro-4-isopropoxy benzoic acid
Steps A: 3-chloro-4-isopropoxy essence of Niobe
In 1.42g (7.63mmol) 3-chloro-4-methyl hydroxybenzoate, 585 μ L (7.63mmol) 2-propanol and the solution of 3.0g (11.45mmol) triphenylphosphine in 20mL THF, add 2.25mL (11.45mmol) diisopropyl azodiformate in 0 ℃.Make this mixture be warmed to room temperature, and stirred 16 hours.Remove and desolvate.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+M tube purification, as eluant, obtain this title compound of 1.77g (100%) with 1: 19 v/v EtOAc/ hexane: 1H NMR δ 1.41 (d, J=6.2,6H), 4.63-4.70 (m, 1H), 6.93 (d, J=8.7,1H), 7.89 (dd, J=2.2,8.6,1H), 8.05 (d, J=2.0,1H).
Step B:3-chloro-4-isopropoxy benzoic acid
Use is similar to relevant carboxylic acid 2 described methods, replaces 3-fluoro-4-isobutyl-benzene methyl formate with 3-cyano group-4-isopropoxy essence of Niobe in step B: 1H NMR δ 1.43 (d, J=5.9,6H), 4.66-4.73 (m, 1H), 6.96 (d, J=8.9,1H), 7.97 (dd, J=2.1,8.7,1H), 8.12 (d, J=2.0,1H), 11.7 (br.s, 1H).
Carboxylic acid 14-15
Use is similar to relevant carboxylic acid 13 described methods, replaces the 2-propanol with suitable purification in steps A, makes following carboxylic acid intermediate.
Figure A20058003626500601
Carboxylic acid 16
4-(4,4-difluoro cyclohexyl) benzoic acid
Steps A: trifluoromethanesulfonic acid 1,4-dioxo spiro [4.5] last of the ten Heavenly stems-7-alkene-8-base ester
To N, in the solution of N-lithium diisopropylamine (30.6mmol) in 30mL THF, drip 1 in-78 ℃, 4-dioxo spiro [4.5] last of the ten Heavenly stems-8-ketone (4.06g, 26.0mmol) solution in 15mLTHF.The gained mixture was stirred 25 minutes at-78 ℃, and (12.0g, 30.5mmol) drips of solution in 15mL THF adds wherein 2-(N, N-two (trifluoromethyl sulfonyl) amino)-5-chloropyridine then.In-78 ℃ stir 2.5 hours after, by adding 10mL 1NNaHCO 3The aqueous solution stopped reaction.With this mixture at Et 2O (200mL) and 1N NaHCO 3Distribute (200mL).Organic layer is separated, use MgSO 4Drying, and concentrate.At the enterprising circumstances in which people get things ready for a trip spectrometry of Biotage40M tube purification, as eluant, obtain this title compound of 4.62g (61%) with 1: 9 v/v EtOAc/ hexane.
Step B:4-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-7-alkene-8-yl) benzoic acid
(0.69g, 3.53mmol) and trifluoromethanesulfonic acid 1,4-dioxo spiro [4.5] last of the ten Heavenly stems-(1.02g 3.53mmol) in the solution in 14mL DMF, adds 7mL 2N Na to 7-alkene-8-base ester to 4-carboxyl phenyl boric acid 2CO 3(159mg is 0.61mmol) with three (dibenzalacetone) palladium (0) (68mg, 74.2 μ mol) for aqueous solution, triphenylphosphine.Stir 3 hours then in stirring at room after 16 hours in 80 ℃, this mixture is concentrated and at 100mL Et 2O and 150mL H 2Distribute between the O water.Water layer is separated, be acidified to pH～2-3, and use CH with dense HCl 2Cl 2(2 * 100mL) extractions.Organic layer is merged, use Na 2SO 4Dry and concentrated.With residue recrystallize from 10mL EtOAc, obtain this title compound of 353mg (38%).
Step C:4-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-7-alkene-8-yl) essence of Niobe
With 4-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-7-alkene-8-yl) benzoic acid (572mg, 2.20mmol), iodomethane (140 μ L, 2.24mmol) and cesium carbonate (710mg, 2.17mmol) mixture in 6mL DMF was in stirring at room 16 hours.With this mixture H 2O (10mL) dilution, and use Et 2O (100mL) extraction.Organic layer is separated, use MgSO 4Drying, and concentrate.Be to carry out chromatography purification on Biotage 40S tube, as eluant, obtain this title compound of 399mg (72%) with 3: 17 v/v EtOAc/ hexanes.
Step D:4-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-yl) essence of Niobe
With 4-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-7-alkene-8-yl) essence of Niobe (514mg, 1.87mmol) and 10%Pd/C (127mg) at 1: 2 v/v EtOAc/CH of 15mL 3Mixture among the OH is at 45Psi H 2Shook 6.5 hours down with the Pa Er shaking machine.Catalyst is filtered by the kieselguhr cake, and wash with a large amount of EtOAc.Filtrate is concentrated, obtain this title compound of 480mg.
Step e: 4-(4-oxo cyclohexyl) essence of Niobe
(480mg 1.73mmol) in the solution in 8mL THF, adds 4mL 1N HCl aqueous solution to 4-(1,4-dioxo spiro [4.5] last of the ten Heavenly stems-8-yl) essence of Niobe.This mixture was also concentrated in stirring at room in 21 hours.Residue at 50mL Et 2O and 50mL 1N NaHCO 3Distribute between the aqueous solution.Organic layer is separated, use MgSO 4Drying, and concentrate.At the enterprising circumstances in which people get things ready for a trip spectrometry of Biotage40S tube purification, as eluant, obtain this title compound of 343mg (85%) with 1: 9 v/v EtOAc/ hexane.
Step F: 4-(4,4-difluoro cyclohexyl) essence of Niobe
Use is similar to relevant carboxylic acid 4 described methods, replaces (3R)-3-(4-bromophenyl) Ketocyclopentane with 4-(4-oxo cyclohexyl) essence of Niobe in step B, makes this title compound.
Step G:4-(4,4-difluoro cyclohexyl) benzoic acid
Use is similar to relevant carboxylic acid 1 described method, replaces (4-(4-fluorophenyl)-5-trifluoromethyl) thiophene-2-carboxylic acid ethyl ester with 4-(4,4-difluoro cyclohexyl) essence of Niobe in step C, makes this title compound: 1H NMR (CD 3OD) δ 1.82 (m, 2H), 1.94 (m, 4H), 2.16 (m, 2H), 2.78 (m, 1H), 7.36 (d, J=8.2,2H), 7.96 (d, J=8.2,2H).
The preparation of embodiment
Embodiment 1
Trans-2-(4-(5-(4-(2-methyl-propyl) phenyl)-1,2,4- diazole-3-yl) phenyl)-4-pyrrolidine acetic acid
Steps A: trans-5-(4-(5-(4-(2-methyl-propyl) phenyl)-1,2,4- diazole-3-yl) phenyl)-2-oxo-3-methyl pyrrolidineacetate
With amidine oxime 1,4-(2-methyl-propyl) benzoic acid (127mg, 0.71mmol), 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (149mg, 0.78mmol) and the I-hydroxybenzotriazole hydrate (44mg, 0.32mmol) solution in acetonitrile (10mL) was in stirring at room 1 hour.This mixture is concentrated, and, as eluant, obtain the ester intermediate with EtOAc at the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+S tube purification.
The solution backflow of above-mentioned ester in dimethylbenzene (10mL) concentrated in 2 hours then.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+S tube purification, as eluant, obtain this title compound of 63mg (22% 3 step) with 3: 2 v/v EtOAc/ hexanes, be white solid: 1H NMR δ 0.94 (d, J=6.7,6H), 1.92-1.97 (m, 1H), 2.33-2.59 (m, 5H), 2.89 (dd, J=4.0,16.9,1H), 2.97-3.00 (m, 1H), 3.70 (s, 3H), 4.85 (dd, J=3.0,8.7,1H), 6.08 (br.s, 1H), 7.33 (d, J=8.2,2H), 7.42 (d, J=8.2,2H), 8.12 (d, J=8.2,2H), 8.18 (d, J=8.3,2H).
Step B: trans-2-(4-(5-(4-(2-methyl-propyl) phenyl)-1,2,4- diazole-3-yl) phenyl)-4-pyrrolidine acetic acid
(63mg, 0.15mmol) (26mg is 0.17mmol) at CH with fluoboric acid trimethyl oxygen  with above-mentioned lactams 2Cl 2Solution (10mL) is in stirred overnight at room temperature.Then with the saturated NaHCO of this reactant mixture 3Solution (20mL) washing.Water layer is separated, and use CH 2Cl 2(3 * 20mL) extractions.Organic layer is merged, use MgSO 4Drying concentrates, and obtains imido ether, uses it for next step and will not be further purified.
(solution among the 1.0M in THF, 727 μ L 0.73mmol) are added to gained imido ether and a small amount of bromocresol green at CH sodium cyanoborohydride solution 3In the solution in the OH (10mL).1, the solution in the 4-dioxane (2.0M) is added in this reactant mixture HCl, so as with color keep yellow (pH～3-4), and with the gained mixture in stirring at room 4 hours.This mixture is poured into saturated NaHCO 3Solution (20mL) and CH 2Cl 2(20mL), and water layer further used CH 2Cl 2(3 * 20mL) extractions.Organic layer is merged, use Na 2SO 4Dry and concentrated, obtain rough amine (70mg).
Sodium hydroxide (5.0N, 110 μ L) is added to rough amine, and (23mg is 0.05mmol) in the solution in EtOH (5.0mL), and in stirring at room 30 minutes.Reactant mixture is concentrated, and, obtains embodiment 1 (9.7mg, 44%) residue HPLC purification: 1H NMR (CD 3OD) δ 0.88 (s, 6H), 1.86-1.91 (m, 1H), 2.23-2.29 (m, 1H), 2.44-2.64 (m, 5H), 2.93-2.99 (m, 1H), 3.12 (dd, J=7.9,11.8,1H), 3.70 (dd, J=7.6,11.8,1H), 4.85 (t, J=8.6,1H), 7.35 (d, J=8.3,2H), 7.60 (d, J=8.5,2H), 8.06 (d, J=8.5,2H), 8.18 (d, J=8.5,2H).
Embodiment 2
Cis-2-(4-(5-(4-(2-methyl-propyl) phenyl)-1,2,4- diazole-3-yl) phenyl)-4-pyrrolidine acetic acid
With being similar to the method for describing among the embodiment 1, in steps A, replace amidine oxime 1 with amidine oxime 2, make embodiment 2: 1H NMR (CD 3OD) δ 1.38 (s, 9H), 2.07 (q, J=12.3,23.8,1H), and 2.61-2.74 (m, 3H), 2.89-3.00 (m, 1H), 3.23-3.27 (m, 1H), 3.72-3.76 (m, 1H), 4.79-4.83 (m, 1H), 7.66 (d, J=8.5,2H), 7.69 (d, J=8.5,2H), 8.14 (d, J=8.5,2H), 8.23 (d, J=8.5,2H).
Embodiment 3
Anti-form-1-methyl-2-(4-(5-(4-(2-methyl-propyl) phenyl)-1,2,4- diazole-3-yl) phenyl)-4-pyrrolidine acetic acid
With trans-2-(4-(5-(4-(2-methyl-propyl) phenyl)-1,2,4- diazole-3-yl) phenyl)-(embodiment 1 for the 4-methyl pyrrolidineacetate, step B, 18mg, 0.04mmol), iodomethane (3 μ L, 0.05mmol) and potassium carbonate (30mg, 0.21mmol) mixture in 2.0mL DMF in 100 ℃ 1 hour.After being cooled to room temperature, this reactant mixture is filtered by the kieselguhr cake, and with residue CH 2Cl 2(50mL) washing.Filtrate is used the salt water washing, use Na 2SO 4Dry and concentrated, obtain rough amine.
In the solution of above-mentioned rough amine in EtOH (4.0mL), add NaOH (86 μ L 5.0N NaOH, 0.43mmol).After 16 hours, interior gained reactant mixture concentrates in stirring at room.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+S tube purification, with having 1.0%NH 43: 17 v/vCH of OH 3OH/CH 2Cl 2As eluant, obtain this title compound of 8.0mg (44% liang of step), be white solid: 1H NMR δ 0.88 (d, J=6.7,6H), 1.88 (m, 1H), 2.28 (m, 1H), 2.52-2.61 (m, 5H), 2.69 (s, 3H), 2.99 (m, 2H), 3.91 (dd, J=6.9,10.8,1H), 4.43 (t, J=9.1,1H), 7.36 (d, J=8.2,2H), 7.63 (d, J=8.2,2H), 8.07 (d, J=8.2,2H), 8.21 (d, J=8.5,2H).
Embodiment 4
Trans-2-(4-(5-(4-(4-fluorophenyl)-5-trifluoromethyl-2-thienyl)-1,2,4- diazole-3-yl) phenyl)-4-pyrrolidine acetic acid
Steps A: trans-3-pi-allyl-5-(4-(5-(4-(4-fluorophenyl)-5-trifluoromethyl-2-thienyl)-1,2,4- diazole-3-yl) phenyl) pyrrolidin-2-one
With being similar to the method for describing among the embodiment 1, in steps A, replace amidine oxime 1 with amidine oxime 3 respectively, replace 4-(2-methyl-propyl) benzoic acid with 4-(4-fluorophenyl)-5-(trifluoromethyl) thiophene-2-carboxylic acid, make this title compound: 1H NMR (CD 3OD) δ 2.16 (m, 1H), 2.28 (m, 1H), 2.42 (m, 1H), 2.63 (m, 2H), 4.79 (m, 1H), 5.12 (m, 2H), 5.80 (m, 1H), 6.01 (s, 1H), 7.17 (t, J=8.7,2H), 7.44 (m, 4H), 7.88 (m, 1H), 8.14 (d, J=8.4,2H).
Step B: trans-2-(4-(5-(4-(4-fluorophenyl)-5-trifluoromethyl-2-thienyl)-1,2,4- diazole-3-yl) phenyl)-4-methyl pyrrolidineacetate
Ruthenic chloride (III) hydrate (1mg, 4.4mol) be added to trans 3-pi-allyl-5-(4-(5-(4-(4-fluorophenyl)-5-trifluoromethyl-2-thienyl)-1,2,4- diazole-3-yl) pyrrolidin-2-one (103mg phenyl), 0.20mmol) and sodium metaperiodate (193mg is 0.90mmol) at 2: 2: 3 v/v/vCCl 4/ CH 3CN/H 2In the solution in the mixed solvent of O (7.0mL).With this mixture in stirring at room 1 hour, then at H 2O (20mL) and CH 2Cl 2Distribute (20mL).Water layer is separated, and use CH 2Cl 2(3 * 20mL) extractions.Organic layer is merged, use Na 2SO 4Dry and concentrated, obtain rough acid, be colourless serosity.
(solution of 2.0M in hexane, 48 μ L 0.10mmol) are added to crude acid at 7: 2 v/v benzene/CH (trimethyl silyl) Azimethylene. 3In the solution in the mixed solvent of OH (9mL).After 30 minutes, this reactant mixture is concentrated.At the enterprising circumstances in which people get things ready for a trip spectrum of Biotage 40+S tube purification, as eluant, obtain this title compound of 20.0mg (18% liang of step) with 3: 2 v/v EtOAc/ hexanes, be white solid: 1H NMR δ 2.36 (m, 1H), 2.44-2.58 (m, 2H), 2.90 (dd, J=4.0,7.0,1H), 2.98 (m, 1H), 3.71 (s, 3H), 4.85 (dd, J=2.9,9.0,1H), 5.89 (s, 1H), 7.17 (d, J=8.6,2H), 7.42-7.47 (m.4H), 7.89 (m, 1H), 8.15 (d, J=8.2,2H).
Step C: trans-2-(4-(5-(4-(4-fluorophenyl)-5-trifluoromethyl-2-thienyl)-1,2,4- diazole-3-yl) phenyl)-4-pyrrolidine acetic acid
(4-(5-(4-(4-fluorophenyl)-5-trifluoromethyl-2-thienyl)-1,2,4- diazole-3-yl) phenyl)-(20mg, 0.04mmol) (6.5mg is 0.04mmol) at 5mL CH with fluoboric acid trimethyl oxygen  for the 4-methyl pyrrolidineacetate with trans-2- 2Cl 2In solution in stirred overnight at room temperature.With this mixture saturated NaHCO of 20mL 3Washing, and with water layer CH 2Cl 2(3 * 20mL) extractions.Organic layer is merged, use Na 2SO 4Dry and concentrate, obtain imido ether, use it for next step and will not be further purified.
(solution of 1.0M in THF, 367 μ L 0.37mmol) are added to above-mentioned imido ether and a small amount of bromocresol green at CH sodium cyanoborohydride solution 3In the solution in the OH (10mL).1, the solution in the 4-dioxane (2.0M) is added in this reactant mixture HCl, so that the color of mixture is kept yellow.With the gained mixture in stirring at room 4 hours.Pour saturated NaHCO into 3Solution and CH 2Cl 2In, and water layer further used CH 2Cl 2(3 * 20mL) extractions.Organic layer is merged, use Na 2SO 4Dry and concentrate, obtain rough amine, use it for next step and will not be further purified.
(5.0N, 94 μ L) are added in the solution of above-mentioned amine in EtOH (4.0mL) sodium hydroxide, and in stirred overnight at room temperature.Reactant mixture is directly carried out purification with HPLC, obtains this title compound (11mg, 58% 3 step): 1H NMR (CD 3OD) δ 2.26 (m, 1H), 2.49 (m, 1H), 2.61 (m, 1H), 2.96 (m, 1H), 3.13 (m, 1H), 3.71 (dd, J=7.7,11.8,1H), 4.85 (t, J=8.6,1H), 7.16-7.20 (m, 2H), 7.46-7.50 (m, 2H), 7.61 (d, J=8.4,2H), 8.00 (m, 1H), 8.18 (d, J=8.2,2H).
Embodiment 5
Trans-2-(4-(5-(4-cyclopenta phenyl)-1,2,4- diazole-3-yl) phenyl)-4-pyrrolidine acetic acid
Steps A: trans-N-tert-butoxycarbonyl-2-(4-(5-(4-cyclopenta phenyl)-1,2,4- diazole-3-yl) phenyl)-4-methyl pyrrolidineacetate
With being similar to the method for describing among the embodiment 1, in steps A, replace amidine oxime 1 with amidine oxime 4 respectively, replace 4-(2-methyl-propyl) benzoic acid with 4-cyclopenta benzoic acid, make this title compound: 1H NMR δ 1.21 (s, 9H), 1.47-1.87 (m, 6H), 2.05-2.15 (m, 3H), 2.41-2.48 (m, 2H), 2.70 (m, 1H), 3.06-3.31 (m, 2H), 3.67 (s, 3H), 3.93 (m, 1H), 4.91 (m, 1H), 5.07 (m, 1H), 7.30 (d, J=8.0,2H), 7.41 (d, J=8.3,2H), 8.12 (m, 4H).
Step B: trans-2-(4-(5-(4-cyclopenta phenyl)-1,2,4- diazole-3-yl) phenyl)-4-pyrrolidine acetic acid
With trans-N-tert-butoxycarbonyl-2-(4-(5-(4-cyclopenta phenyl)-1,2,4- diazole-3-yl) phenyl)-4-methyl pyrrolidineacetate (4.4mg, 8.3mol) at 2.5mL 20%TFA at CH 2Cl 2In solution in solution in stirring at room 1 hour, concentrate then.Residue is dissolved among the 5.0mL EtOH again, and the adding sodium hydroxide (189 μ L, 5.0N, 0.95mmol)., after 1 hour reactant mixture is concentrated in stirring at room, and residue is carried out purification with HPLC, obtain this title compound of 3.5mg (100%): 1H NMR (CD 3OD) δ 1.60 (m, 2H), 1.69 (m, 2H), 1.81 (m, 2H), 2.06 (m, 2H), 2.26 (m, 1H), 2.46 (m, 1H), 2.58 (m, 2H), 2.96 (m, 1H), 3.07 (m, 1H), 3.12 (dd, J=7.7,11.9,1H), 3.70 (dd, J=7.7,11.8,1H), 4.84 (t, J=8.6,1H), 7.44 (d, J=8.2,2H), 7.60 (d, J=8.4,2H), 8.06 (d, J=8.4,2H), 8.18 (d, J=8.2,2H).
Embodiment 6-19
Following examples are to use and are similar to the method for describing among the embodiment 5, replace 4-(2-methyl-propyl) benzoic acid to prepare with suitable carboxylic acid in steps A.Embodiment 9 and precursor-embodiment 5 of 10, the product in the steps A is isolating on Chiralcel OD 20 * 250mm post, and with 85: 15 v/v heptane/EtOH isocratic elution 30 minutes, flow velocity was 8.0mL/ minute, and the UV wavelength is at 254nm.Under this separation condition, the retention time of the precursor of embodiment 9 is shorter than the precursor of embodiment 10.
Figure A20058003626500671
Figure A20058003626500681
Embodiment 20-27
Following examples are to use and are similar to the method for describing among the embodiment 5, use amidine oxime 5 to replace amidine oximes 4 in steps A, replace 4-cyclopenta benzoic acid to prepare with the carboxylic acid that uses.
Figure A20058003626500692
Figure A20058003626500701
Embodiment 28
Trans-2-(4-(5-(4-cyclohexyl phenyl)-1,2,4- diazole-3-yl) phenyl)-4-pyrrolidine acetic acid
Steps A: trans-N-tert-butoxycarbonyl-2-(4-(5-(4-cyclohexyl phenyl)-1,2,4- diazole-3-yl) phenyl)-4-(2-acrylic)-pyrrolidine
With being similar to the method for describing among the embodiment 1, in steps A, replace amidine oxime 1 with amidine oxime 6 respectively, replace 4-(2-methyl-propyl) benzoic acid with 4-cyclohexyl benzene formic acid, make this title compound: 1H NMR δ 1.13-1.58 (m, 15H), 1.77-1.96 (m, 7H), 2.05-2.63 (m, 3H), 3.25 (m, 1H), 3.83 (m, 1H), 4.91-5.07 (m, 3H), 5.74 (m, 1H), 7.29 (d, J=8.0,2H), 7.38 (d, J=8.3,2H), 8.12 (m, 4H).
Step B: trans-2-(4-(5-(4-cyclohexyl phenyl)-1,2,4- diazole-3-yl) phenyl)-4-pyrrolidine acetic acid
Ruthenic chloride (III) hydrate (0.1mg, 0.5mol) be added to trans-N-tert-butoxycarbonyl-2-(4-(5-(4-cyclohexyl phenyl)-1,2,4- diazole-3-yl) phenyl)-4-(2-acrylic)-pyrrolidine (12mg, 0.02mmol) (23mg is 0.11mmol) at 2: 2: 3 v/v/vCCl with sodium metaperiodate 4/ CH 3CN/H 2In the solution in the admixture solvent of O (7.0mL).With this mixture in stirring at room after 1 hour, then at H 2O (10mL) and CH 2Cl 2Distribute (10mL).Water layer is separated, and use CH 2Cl 2(3 * 10mL) extractions.Just organic layer merges, and uses Na 2SO 4Dry and concentrated, obtain rough acid, be colourless serosity.
With the CH of above-mentioned crude acid at 2.5mL 20% trifluoroacetic acid 2Cl 2Solution in the solution was in stirring at room 30 minutes.Remove and desolvate, and residue is carried out purification with HPLC: 1H NMR δ 1.26 (m, 2H), 1.43 (m, 4H), 1.74 (m, 2H), 1.83 (m, 4H), 2.25 (m, 1H), 2.55 (m, 4H), 2.95 (m, 1H), 3.12 (dd, J=8.0,11.8,1H), 3.69 (dd, J=7.7,12.3,1H), 4.83 (m, 1H), 7.41 (d, J=8.3,2H), 7.60 (d, J=8.3,2H), 8.07 (d, J=8.3,2H), 8.18 (d, J=8.3,2H).
Embodiment 29-32
Following examples are to use and are similar to the method for describing among the embodiment 18, replace 4-cyclohexyl benzene formic acid to prepare with suitable carboxylic acid in steps A.
Figure A20058003626500711
Figure A20058003626500721
Embodiment 33
Trans-2-(4-(5-(4-((1R)-3,3-difluoro cyclopenta) phenyl)-1,2,4- diazole-3-yl)-3-methyl-phenyl)-4-pyrrolidine acetic acid
With being similar to the method for describing among the embodiment 4, in steps A, replace amidine oxime 3 with amidine oxime 7 respectively, replace 4-(4-fluorophenyl)-5-(trifluoromethyl) thiophene-2-carboxylic acid with 4-((1R)-3,3-difluoro cyclopenta) benzoic acid, make this title compound: 1H NMR δ 1.87 (m, 1H), 2.25 (m, 5H), 2.46 (m, 3H), 2.61 (m, 1H), 2.65 (s, 3H), 2.96 (m, 1H), 3.12 (dd, J=7.9,10.8,1H), 3.41 (m, 1H), 3.71 (dd, J=7.7,12.0,1H), 4.81 (m, 1H), 7.40-7.50 (m, 4H), 8.10-8.12 (m, 3H).
Embodiment 34,35
These embodiment are diastereomers of embodiment 33.The precursor of embodiment 33-trans-N-tert-butoxycarbonyl-2-(4-(5-(4-((R)-3,3-difluoro cyclopenta) phenyl)-1,2,4- diazole-3-yl)-3-methyl-phenyl)-the 4-methyl pyrrolidineacetate is isolating on Chiralpak AD 20 * 250mm post, with 50: 50 v/v heptane/EtOH isocratic elution 50 minutes, flow velocity is 7.0mL/ minute, and the UV wavelength is at 254nm.Under this separation condition, the retention time of the precursor of embodiment 34 is shorter than the retention time of the precursor of embodiment 35.
Figure A20058003626500722
Figure A20058003626500731
Biologic activity
Can be with following test to the S1P of The compounds of this invention 1/ Edg1, S1P 3,/Edg3, S1P 2/ Edg5, S1P 4/ Edg6 or S1P 5/ Edg8 activity is assessed:
The test that combines of part and Edg/S1P receptor
Comprising 50mMKH with having the active thick yeast extract in E.C. 2.7.1.91 2PO 4, 1mM mercaptoethanol, 1mM Na 3VO 4, 25mM KF, 2mM semicarbazides 1mM Na 2EDTA, 5mM MgCl 2, 50mM sphingol, 0.1% TritonX-114 and 1mCi γ 33P-ATP (NEN; Specific activity 3000Ci/mmol) in the reactant mixture by γ 33P-ATP and sphingol carry out 33The enzymatic synthesis of P-sphingosine-1-phosphate ester.This product is extracted and right with butanols with HPLC 33P-sphingosine-1-phosphate ester carries out purification.
(Specialty Media, Lavallette NJ) gather in the crops the cell of expressing the EDG/S1P receptor with the solution that dissociates that does not contain enzyme.It is washed once in cold PBS and it is suspended in the HEPES-Na by 50mM, pH 7.5,5mM MgCl 2, 1mM CaCl 2With 0.5% not fatty acids BSA formed in conjunction with in the test buffer agent.Will 33P-sphingosine-1-phosphate ester carries out sonication with 0.1nM sphingosine-1-phosphate ester in conjunction with test buffer agent; To the 100 μ l cells (1 * 10 that are arranged in 96 hole microtitration wares 6Add the described ligand mixture of 100 μ l in the individual cell/ml).Under the blended situation of gentleness, make it at room temperature in conjunction with 60 minutes.Then, with Packard Filtermate Universal Harvester with cell harvesting to the GF/B filter plate.With this filter plate after dry 30 minutes, in each hole, add 40 μ l Microscint 20 and on Wallac Microbeta scintillation counter in conjunction with measuring.Non-specific binding is defined in the amount of remaining radioactive activity under the situation that has the cold sphingosine-1-phosphate ester of 0.5 μ M.
Perhaps, on film, carry out part in conjunction with test by the cell preparation of expressing the Edg/S1P receptor.Come harvesting and it is washed once in cold PBS with the solution that dissociates that does not contain enzyme.Come broken these cells by in ice-cold 20mM HEPES pH 7.4,10mMEDTA, carry out homogenize (scale 5,10 seconds) with Kinematica polytron.These homogenate are suspended in 20mM HEPES pH 7.4 at 4 ℃ of following centrifugal 15min and with piller under 48,000 * g, among the 0.1mM EDTA.After for the second time centrifugal, the piller that this is last is suspended in 20mM HEPESpH 7.4,100mM NaCl, 10mM MgCl 2In.Carry out part as described above in conjunction with test with 0.5 to 2 μ g memebrane protein.
Can be somebody's turn to do at this 33P-sphingosine-1-phosphate ester is in conjunction with agonist and the antagonist of determining the Edg/S1P receptor in the test.Will with the chemical compound of DMSO, methanol or other solvent dilution with comprise 33The probe of P-sphingosine-1-phosphate ester and in the microtitration ware, mix in conjunction with test buffer agent.To the film that wherein adds by the cell preparation of expressing the Edg/S1P receptor, and carry out as shown with 33The combination of P-sphingosine-1-phosphate ester.There is data are analyzed to measure the affinity of these chemical compounds to said receptor in conjunction with quantity and with nonlinear regression software such as MRLCalc (Merck ResearchLaboratories) or PRISM (GraphPad software) under the various concentration chemical compound situations in mensuration.By using by by each receptor (S1P 1/ Edg1, S1P 3/ Edg3, S1P 2/ Edg5, S1P 4/ Edg6, S1P 5/ Edg8) film that makes of cells transfected is measured existing under the situation of said chemical compound 33The bonded level of P-sphingosine-1-phosphate ester is measured the selectivity of chemical compound to the Edg/S1P receptor.
35S-GTP γ S is in conjunction with test
With 35S-GTP γ S is in conjunction with experimental measurement S1P/Edg receptor and the proteic functional coupling of G.The film that will prepare as described in part and the Edg/S1P receptor binding assays (1-10 μ g memebrane protein) comprises 20mM HEPES pH 7.4,100mM NaCl, 10mMMgCl at 200 μ l 2, 5 μ M GDP, 0.1% BSA of fatty acids (Sigma, catalog A8806) not, the sphingosine-1-phosphate ester of various concentration, and 125pM 35S-GTP γ S (NEN; Specific activity 1250Ci/mmol) in 96 hole microtitration wares, cultivates in the volume.It is at room temperature carried out 1 hour combination under the blended situation of gentleness, stop combination by this film being collected on the GF/B filter plate with Packard FiltermateUniversal Harvester.Behind dry 30min with this filter plate, in each hole, add 40 μ l Microscint 20 and at the WallacMicrobeta scintillation counter in conjunction with measuring.
Can be described 35S-GTP γ S is in conjunction with agonist and the antagonist of determining the S1P/Edg receptor in the test.Thereby will join the ultimate density that obtains 0.01nM to 10 μ M in the microtitration ware with the chemical compound of DMSO, methanol or other solvent dilution.To the film that wherein adds by the cell preparation of expressing the S1P/Edg receptor, and as described like that with 35S-GTP γ S carries out combination.When testing under the situation that does not have native ligand or other known agonist, thinking stimulates on the level that is higher than the endogenous level 35The bonded chemical compound of S-GTP γ S is an agonist, and thinks inhibition 35The chemical compound of the bonded endogenous level of S-GTP γ S is an inverse agonist.Be lower than in existence under the situation of the native ligand of maximum horizontal or known S1P/Edg receptor stimulating agent and use 35S-GTP γ S is in conjunction with testing detecting antagonist, and these chemical compounds have reduced in this case 35The bonded level of S-GTP γ S.Be used in measure under the situation that has various concentration chemical compounds measure the effectiveness of chemical compound in conjunction with quantity as agonist, inverse agonist or the antagonist of S1P/Edg receptor.For agonist is assessed, the stimulation percentage calculation that will be higher than benchmark is for existing combination under the chemical compound situation divided by not existing the combination under the part situation to multiply by 100 form again.Make dose response curve with nonlinear regression curve fitting procedure MRLCalc (Merck ResearchLaboratories), and with EC 50Value defined is for obtaining the required agonist concentration of himself maximal stimulus 50%.By using the film measurement that makes by each receptor cells transfected to exist under the chemical compound situation 35S-GTP γ S measures the selectivity of chemical compound to the S1P/Edg receptor in conjunction with level.
The test of intracellular Ca2+ flux
Measure S1P/Edg receptor and the G proteic functional coupling movable relevant with FLIPR (fluorescence imaging plate reader, molecular device (Fluorescence ImagingPlate Reader, Molecular Devices)) with intracellular Ca2+.Results are expressed the cell of S1P/Edg receptor and it are washed once with test buffer agent (comprise 20mM HEPES, the Hanks Buffered saline solution (BRL) of 0.1%BSA and 710 μ g/ml probenecid (probenicid) (Sigma)).At 37 ℃ and 5%CO 2Down in the identical buffer agent that comprises the calcium sensitive dyestuff Fluo-4 of 500nM (molecular probe) to these cell markings 1 hour.With buffer agent with these cell washings twice, then with it with every hole 1.5 * 10 5Quantity (90 μ l) be coated with and be plated in the 96 hole black microtitration wares that applied polylysin.By the concentration of 2 times of the most final experimental concentration of sphingosine-1-phosphate ester or other agonist dilution being prepared a kind of 96-hole part plate with 200 μ l test buffer agents.This part plate and cell plates are loaded on this FLIPR instrument so that it is analyzed.Make these plate balances to 37 ℃.Begin test in the cell plates by isopyknic part is transferred to, and write down the calcium flux with the interval of 3min.Form pair cell response with area (summation) or maximum peak height (max) is carried out quantitatively.Under the situation that does not have native ligand, by with The suitable solvent chemical compound being diluted and it being transferred in the cell of Fluo-4 labelling to come agonist is assessed.By add native ligand or other S1P/Edg receptor stimulating agent begin calcium current go out before by coming antagonist is assessed in 15 minutes with the cell pretreatment of the chemical compound of various concentration to this Fluo-4 labelling.
Express the preparation of S1P/Edg recipient cell
Any S1P that clones in can be in many ways 1/ Edg1, S1P 3/ Edg3, S1P 2/ Edg5, S1P 4/ Edg6 or S1P 5/ Edg8.These methods comprise without limitation: and (1) RACE PCR clone technology (people such as Frohman, 1988, Proc.Natl.Acad.Sci.USA85:8998-9002).Can be with 5 ' and/or 3 ' RACE produce full-length cDNA sequence; (2) in suitable expression vector system, made up the cDNA library that comprises S1P/Edg after the direct function expression of Edg/S1P cDNA; (3) used by the carrying out of the proteic aminoacid sequence of this S1P/Edg design the degenerate oligonucleotide probe of labelling that the cDNA library that comprises S1P/Edg that makes up in phage or plasmid shuttle vector is screened; (4) with the proteic incomplete cDNA of the described S1P/Edg of coding the cDNA library that comprises S1P/Edg that makes up in phage or plasmid shuttle vector is screened.To be the degenerate oligonucleotide initiator that derives from other the albumen known aminoacid sequence relevant with S1P/Edg albumen by design obtained by the specific pcr amplification of S1P/Edg dna segment this incomplete cDNA; (5) use with mammal S1P/Edg albumen and have the Partial cDNA of homology or oligonucleotide screening in the cDNA library that comprises S1P/Edg of phage or plasmid shuttle vector rebuild.For the pcr amplification of S1P/EdgcDNA, this strategy may also relate to the oligonucleotide that uses gene specific and cause agent; Or (6) with the S1P/Edg nucleotide sequence as stencil design 5 ' and the oligonucleotide of 3 ' gene specific, thereby make and to produce full-length cDNA with known RACE technology, perhaps can with these be used for producing produce the part of coding region with the identical known RACE technology of isolating a kind of part coding region and with it as being used for filtering out a kind of probe from many class cDNA and/or genomic library, thereby isolate the full-length version of the nucleotide sequence of the S1P/Edg that encodes.
Those skilled in the art it is evident that can be with the library of other type and the DNA or the S1P/Edg homologue that are separated the S1P/Edg that encodes by the data base that other cell type or kind type make up.The library of other type comprises the cDNA library that derives from other cell without limitation.
Those skilled in the art it is evident that can be by having the suitable cDNA library of active cell of S1P/Edg or cell line preparation.Can measure that the S1P/Edg relevant with cell is active to be come to be used for isolating the encode cell or the cell line in cDNA library of cDNA of S1P/Edg and to select being used to prepare by any obtainable known test that at first is used for such purpose.
Can carry out the preparation in cDNA library with the known standard technique of prior art.For example can be people such as Sambrook, 1989, molecular cloning: laboratory manual (Molecular Cloning:A Laboratory Manual); Cold Spring Harbor Laboratory, Cold SpringHarbor finds well-known cDNA library construction technology in the New York.Complementary DNA library can also be obtained by many commercial source, and described commercial source comprises ClontechLaboratories without limitation, Inc. and Stratagene.
For the expression in the recombinant host cell, can use the expression vector that comprises the proteic DNA of coding S1P/Edg-sample for S1P/Edg.Thereby such recombinant host cell can be cultivated the form of preparing S1P/Edg or biologically equivalent under suitable condition.Expression vector can comprise the cloning vehicle of cloning vehicle, modification, the plasmid or the virus of particular design without limitation.The mammalian expression vector that obtains by commercial sources may be applicable to that the S1P/Edg of reorganization expresses.
The host cell of reorganization can be protokaryon or eukaryotic cell, comprises antibacterial such as escherichia coli, fungal cell such as yeast, mammalian cell without limitation, comprises the cell line in cattle, pig, monkey and rodent source without limitation; And insect cell, comprise the cell line that derives from fruit bat and silkworm without limitation.
The nucleotide sequence of various S1P/Edg receptors is known in the prior art.For example can be referring to following document:
S1P 1/ Edg1 people
Ela, T. with T.Maciag 1990, inductive a large amount of transcripies have been encoded and have been had polypeptide (An abundanttranscript induced in differentiating human endothelial cells encodes apolypeptide with structural similarities to G-protein coupled receptors) .J.Biol Chem.265:9308-9313 with the structural similarity structure of G-protein-coupled receptor in the human endothelial cell of differentiation, and it here all is incorporated herein by reference.
WO91/15583 is disclosed on October 17th, 1991, and it here all is incorporated herein by reference.
WO99/46277 was disclosed in JIUYUE in 1999 16, and it here all is incorporated herein by reference.
S1P 1/ Edg1 mice
WO0059529 is disclosed on October 12nd, 2000, and it here all is incorporated herein by reference.
US 6,323,333, are authorized in November 27 calendar year 2001, and it here all is incorporated herein by reference.
S1P 1/ Edg1 rat
Lado, D.C., C.S.Browe, A.A.Gaskin, J.M.Borden, and A.J.MacLennan.1994, the clone of rat edg-1 immediate-early gene: expression way has shown function diversity (Cloning of the rat edg-1 immediate-early gene:expressionpattern suggests diverse functions) .Gene 149:331-336, and it here all is incorporated herein by reference.
US 5,585,476, are authorized in 17th at December in 1996, and it here all is incorporated herein by reference.
US 5856,443, are authorized on January 5th, 1999, and it here all is incorporated herein by reference.
S1P 3/ Edg3 people
An, S., T.Bleu, W.Huang, O.G.Hallmark, S.R.Coughlin, E.J.Goetzl 1997, evaluation (the Identification of cDNAs encoding two G protein-coupled receptors for lysosphingolipids FEBS) Lett.417:279-282 of the cDNAs of two kinds of G-protein-coupled receptors of coding lysophosphatide (lysosphingolipids) FEBS, it here all is incorporated herein by reference.
WO 99/60019, is disclosed on November 25th, 1999, and it here all is incorporated herein by reference.
US 6,130,067, and on October 10th, 2000, it here all was incorporated herein by reference.
S1P 3/ Edg3 mice
WO 01/11022, is disclosed in February 15 calendar year 2001, and it here all is incorporated herein by reference.
S1P 3/ Edg3 rat
WO 01/27137, is disclosed in April 19 calendar year 2001, and it here all is incorporated herein by reference.
S1P 2/ Edg5 people
An, S., Y.Zheng, relevant signalling incident (the Sphingosine 1-Phosphate-induced cell proliferation of the inductive hyperplasia of T.Bleu 2000 sphingosine 1-phosphates, survival and G-protein-coupled receptor Edg3 and Edg5 mediation, survival, andrelated signaling events mediated by G Protein-coupled receptors Edg3and Edg5) .J.Biol.Chem 275:288-296, it here all is incorporated herein by reference.
WO 99/35259, is disclosed on July 15th, 1999, and it here all is incorporated herein by reference.
WO99/54351 is disclosed on October 28th, 1999, and it here all is incorporated herein by reference.
WO 00/56135, is disclosed in JIUYUE in 2000 28, and it here all is incorporated herein by reference.
S1P 2/ Edg5 mice
WO 00/60056, is disclosed on October 12nd, 2000, and it here all is incorporated herein by reference.
S1P 2/ Edg5 rat
Okazaki, H., N.Ishizaka, T.Sakurai, K.Kurokawa, K.Goto, M.Kumada, Y.Takuwa 1993, the molecular cloning of the controversial Novel G protein coupled receptor of expressing in cardiovascular system (Molecular cloning of a novel putative Gprotein-coupled receptor expressed in the cardiovascular system) .Biochem.Biophys.Res.Comm.190:1104-1109, it here all is incorporated herein by reference.
MacLennan, A.J., C.S.Browe, A.A.Gaskin, D.C.Lado, G.Shaw1994, the clone of the controversial G protein-coupled receptor that in growth, may relate to and characteristic (Cloning and characterization of a putative G-protein coupled receptorpotentially involved in development) .Mol.Cell.Neurosci.5:201-209, it here all is incorporated herein by reference.
US 5,585,476, are authorized in 17th in December in 1996, and it here all is incorporated herein by reference.
US 5856,443, are authorized on January 5th, 1999, and it here all is incorporated herein by reference.
S1P 4/ Edg6 people
Graler, M.H., G.Bernhardt, M.Lipp 1998 EDG6, a kind of in lymphoid tissue by the Novel G protein coupled receptor relevant of particular expression (a novel G-protein-coupled receptor related to receptors for bioactivelysophospholipids with the biological activity Lysophospholipid Receptor, is specifically expressed in lymphoid tissue) .Genomics53:164-169, it here all is incorporated herein by reference.
WO 98/48016, is disclosed on October 29th, 1998, and it here all is incorporated herein by reference.
US 5,912,144, are authorized on June 15th, 1999, and it here all is incorporated herein by reference.
WO 98/50549, is disclosed on November 12nd, 1998, and it here all is incorporated herein by reference.
US 6,060,272, are authorized on May 9th, 2000, and it here all is incorporated herein by reference.
WO 99/35106, is disclosed on July 15th, 1999, and it here all is incorporated herein by reference.
WO 00/15784, is disclosed on March 23rd, 2000, and it here all is incorporated herein by reference.
WO 00/14233, is disclosed on March 16th, 2000, and it here all is incorporated herein by reference.
S1P 4/ Edg6 mice
WO 00/15784, is disclosed on March 23rd, 2000, and it here all is incorporated herein by reference.
S1P 5/ Edg8 people
Im, D.-S., J.Clemens, T.L.Macdonald, K.R.Lynch 2001, people and mice sphingosine 1-phosphate receptor, S1P 5(Edg-8) characteristic: the structure of sphingosine 1-phosphate receptor-active relation (Characterization of the human and mouse sphingosine1-phsophate receptors, S1P 5(Edg-8): .Biochemistry 40:14053-14060 Structure-Activity relationship ofsphingosine 1-phsophate receptors), it here all is incorporated herein by reference.
WO 00/11166, is disclosed on March 2nd, 2000, and it here all is incorporated herein by reference.
WO 00/31258, is disclosed on June 2nd, 2000, and it here all is incorporated herein by reference.
WO 01/04139, is disclosed in January 18 calendar year 2001, and it here all is incorporated herein by reference.
EP 1 090 925, is disclosed in April 11 calendar year 2001, and it here all is incorporated herein by reference.
S1P 5/ Edg8 rat
Im, D.-S., C.E.Heise, N.Ancellin, B.F.O ' Dowd, G.-J.Shei, R.P.Heavens, M.R.Rigby, T.Hla, S.Mandala, G.McAllister, S.R.George, K.R.Lynch 2000, novel sphingosine 1-phosphate receptor, the characteristic of Edg-8 (Characterizationof a novel sphingosine 1-phsophate receptors, Edg-8) .J.Biol.Cbem.275:14281-14286, it here all is incorporated herein by reference.
WO 01/05829, is disclosed in January 25 calendar year 2001, and it here all is incorporated herein by reference.
The measurement of cardiovascular effect
Can assess the effect of The compounds of this invention in the following method to cardio-vascular parameters:
Measure arterial pressure and intravenous administration chemical compound respectively with instrument and equipment bull rat (body weight is approximately 350g) with femoral artery and venous duct.(55mg/kg ip) anaesthetizes with pentobarbital with animal.Its blood pressure of record and heart rate on Gould Po-Ne-Mah data collecting system.Heart rate is obtained by the tremulous pulse impulse wave.After the laundering period, carry out datum readings (about 20 minutes) and these data are average.With chemical compound intravenous administration (about 5 seconds inject or lasting infusion 15 minutes), after with compound administration, data are carried out record every one minute, write down 60 minutes.Come data are calculated or with heart rate or blood pressure change the area under curve form of time mapping calculated with the form of change of the peak in the heart rate or mean arterial pressure.Data are expressed as mean value SEM.Check with the paired t-of one-sided Si Tudeng itself and reference value are carried out statistics relatively, and think at p＜0.05 time significance.
At Sugiyama, A., N.N.Aye, Y.Yatomi, Y.Ozaki, K.Hashimoto 2000 sphingosine-1-phosphate esters---a kind of naturally occurring biologic activity lysophosphatide is to effect (the Effects of Sphingosine-1-Phosphate of rat cardiovascular system, a naturally occurringbiologically active lysophospholipid, on the rat cardiovascular system) among the .Jpn.J.Pharmacol.82:338-342 S1P is described the effect of rat cardiovascular system, it here all is incorporated herein by reference.
The toxic measurement of chmice acute
Be dissolved in test compound in the nontoxic substrate to (tail vein) administration in every mouse vein and observe its toxicity sign with 0.1ml.Serious sign may comprise death, epilepsy, paralysis or loss of consciousness (unconciousness).Also may find slight poisoning sign, slight poisoning sign can comprise ataxia, bradypnea, anger or active reduction for normal mouse.When noticing these signs, with identical substrate to diluting to drug solns.In an identical manner will this diluted dosed administration in second mice and same its sign of observing.Repeat this process until reaching the dosage that does not produce any sign.Think that it is the adiaphorous level of estimation.With this level an other mice is carried out administration to confirm not exist sign.
The assessment of lymphopenia
As described in chmice acute toxicity is measured, chemical compound carried out administration and after administration, as described as follows the lymphopenia of mice was assessed in 3 hours.Using CO 2When making the mice loss of consciousness, open its chest, get 0.5ml blood, with EDTA blood is stablized immediately and with the clinical hematology automatic analyzer (H that is used to carry out the murine differential blood count that has carried out calibration by direct cardiac puncture 2000, CARESIDE, Culver City CA) its hematology is assessed.Compare confirmed test to treat the reduction of medium-sized lymphocyte by hematologic parameter and three mices with matrix treatments with three mices.Modification with above-mentioned dilution process is determined the dosage that this assessment is used by toleration.For this purpose, wish no effect, can accept slight effect, will produce the dosage serial dilution of serious toxicity to the level that only produces slight effect.
The external activity of embodiment
As by in above-mentioned test, measure its as S1P 1Active proved such of/Edg1 receptor effective as selective agonist (for the S1PR3/Edg3 receptor), embodiment disclosed herein can be used as immunomodulator.As above-mentioned 35S-GTP γ S in conjunction with the test in the estimation to S1P 1The EC of/Edg1 receptor 50With to S1P 3The EC of/Edg3 receptor 50Ratio record like that, embodiment disclosed herein is particularly to S1P 1The selectivity ratios of/Edg1 receptor is to S1PR 3The selectivity of/Edg3 receptor is high more than 100 times and as by above-mentioned 35S-GTP γ S in conjunction with test estimate like that, it is to S1P 1The bonded EC of/Edg1 receptor 50Be lower than 50nM.

Claims (22)

1. formula I chemical compound
Figure A2005800362650002C1
Or its officinal salt, wherein:
N is 0,1 or 2;
M is 0,1 or 2, and when m was 0, the A Direct Bonding was on the azetidine shown in the formula I (n=0), pyrrolidine (n=1) or piperidines (n=2) like this;
R 1, R 2, R 3And R 4Be independently selected from :-H ,-F, C 1-C 4Alkyl, C 1-C 4Perfluoroalkyl ,-Cl ,-Br, C 1-C 8Alkoxyl and-OCF 3
R 5And R 6Be independently selected from :-H ,-OH ,-F, C 1-C 4Alkyl and C 1-C 4Perfluoroalkyl;
R 7Be selected from: phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl and thienyl, each described group is optional to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-CN ,-OH ,-NR 8R 9,-NO 2, phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Alkoxyl, C 3-C 6Cycloalkyloxy, C 1-C 6Alkylthio group and C 2-C 6Acyloxy,
Wherein said phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Alkoxyl, C 3-C 6Cycloalkyloxy, C 1-C 6Alkylthio group and C 1-C 6Acyloxy is optional respectively to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-OH and C 1-C 5Alkoxyl;
R 8And R 9Be independently selected from: C 1-C 6Alkyl, C 1-C 6Alkenyl and C 1-C 6Alkynyl, each described group is optional to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-OH and C 1-C 5Alkoxyl, perhaps
R 8And R 9Can form the optional saturated monocycle that contains 1 or 2 oxygen atom with the nitrogen-atoms that they connected with 3-8 atom, described ring optional by 1-3 be independently selected from following substituent group replacement :-F ,-Cl ,-Br ,-I ,-OH and C 1-5Alkoxyl;
X, Y and Z are independently selected from :-C=,-CH-,-O-,-N=,-NH-,-N (R 10)-and-S-, the gained ring is fragrant heterocycle like this;
R 10Be selected from: C 1-C 6Alkyl, C 1-C 6Alkenyl and C 1-C 6Alkynyl, each described group is optional to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-OH and C 1-C 5Alkoxyl;
A is selected from :-CO 2H ,-PO 3H 2,-PO 2H 2,-SO 3H ,-CONHSO 2R 11,-PO (R 11) OH,
Figure A2005800362650003C1
R 11Be selected from: C 1-C 4Alkyl, phenyl ,-CH 2OH and CH (OH)-phenyl; And
Each R 12Be independently selected from :-H and-CH 3
2. the chemical compound of claim 1, wherein A is-CO 2H.
3. the chemical compound of claim 1, wherein n is 1.
4. the chemical compound of claim 1, wherein m is 1.
5. the chemical compound of claim 1, wherein X is-N=, Y is-N=, and Z is-O-that formed like this ring is 1,2,4- diazole.
6. the chemical compound of claim 1, wherein R 7Be phenyl, described phenyl is optional to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-CN ,-OH ,-NR 7R 8,-NO 2, phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Alkoxyl, C 3-C 6Cycloalkyloxy, C 1-C 6Alkylthio group and C 2-C 6Acyloxy,
Wherein said phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 2-C 6Alkenyl, C 2-C 6Alkynyl, C 1-C 6Alkoxyl, C 3-C 6Cycloalkyloxy, C 1-C 6Alkylthio group and C 1-C 6Acyloxy is optional respectively to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I ,-OH and C 1-C 5Alkoxyl.
7. the chemical compound of claim 1, wherein said chemical compound are the chemical compounds of formula Ia representative
Figure A2005800362650004C2
Or its officinal salt, wherein:
P is 0,1 or 2;
R aBe selected from: phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 1-C 6Alkoxyl and C 3-C 6Cycloalkyloxy, wherein said phenyl, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 1-C 6Alkoxyl and C 3-C 6Cycloalkyloxy is optional respectively to be independently selected from following substituent group by 1-3 and to replace :-F ,-Cl ,-Br ,-I and-OH; And
R bBe selected from :-F ,-Cl ,-Br ,-I ,-CN ,-CH 3,-OCH 3,-CF 3, acetenyl ,-NO 2With-NH 2
8. the chemical compound of claim 7, wherein p is 0 or 1, and R bBe selected from :-F ,-Cl and-CF 3
9. the chemical compound of claim 8, wherein R aBe selected from: C 3-C 5Alkyl, cyclopenta, cyclohexyl, C 2-C 4Alkoxyl, cyclopentyloxy and cyclohexyloxy, each described group is optional to be replaced by 1-3 fluorine.
10. be selected from following table chemical compound stereoisomer mixture or do not contain the independent stereoisomer of the pure form basically of other stereoisomer:
Figure A2005800362650005C1
Figure A2005800362650006C1
Figure A2005800362650007C1
Figure A2005800362650008C1
Figure A2005800362650009C1
Or the officinal salt of any above-claimed cpd.
11. treat the method for immunoregulatory abnormality in the mammalian subject that needs such treatment, described method comprises with the amount of the described immunoregulatory abnormality of effective treatment uses the formula I chemical compound of claim 1 for described patient.
12. the method for claim 11, wherein said immunoregulatory abnormality is to be selected from: the autoimmunity or the chronic inflammatory disease of systemic lupus erythematosus, chronic rheumatoid arthritis, type i diabetes, inflammatory bowel, biliary cirrhosis, uveitis, multiple sclerosis, Crohn disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmunity myositis, Wei Genashi granuloma, ichthyosis, Ge Leifusishi oculopathy and asthma.
13. the method for claim 11, wherein said immunoregulatory abnormality are bone marrow or organ-graft refection or graft versus host disease.
14. the method for claim 11, wherein said immunoregulatory abnormality is selected from: the transplanting of organ or tissue; the graft versus host disease that causes by transplanting; comprise rheumatoid arthritis; systemic lupus erythematosus is in interior autoimmunity syndrome; struma lymphomatosa; multiple sclerosis; myasthenia gravis; type i diabetes; uveitis; posterior uveitis; allergic encephalitis; glomerulonephritis; the metainfective autoimmune disease that comprises rheumatic fever and metainfective glomerulonephritis; inflammatory and hyperplasia dermatoses; psoriasis; atopic dermatitis; contact dermatitis; eczematoid dermatitis; seborrheic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; nodular vasculitis; erythema; eosinophilia on the skin; lupus erythematosus; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; the uveitis relevant with Behcet; keratitis; herpetic keratitis; keratoconus; dystrophia epithelialis corneae; corneal leukoma; ocular pemphigus; Mooren's ulcer; scleritis; Ge Leifusishi oculopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergy; the reversibility obstructive airway diseases; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or chronic and refractory asthma; late period asthma and airway hyperreactivity; bronchitis; gastric ulcer; the vascular lesion that causes by ischemic disease and thrombosis; ischemic bowel disease; inflammatory bowel; necrotizing enterocolitis; the small intestinal infringement relevant with thermal burn; celiac disease; proctitis; the eosinophilic gastroenteritis; mastocytosis; Crohn disease; ulcerative colitis; migraine; rhinitis; eczema; interstitial nephritis; goodpasture syndrome; hemolytic uremic syndrome; diabetic nephropathy; the sugar polymyositis; guillain-Barre syndrome; Meniere; polyneuritis; polyneuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's disease; simple property erythroid aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; erythrocyte takes place can not; osteoporosis; sarcoidosis; fibroid lung; idiopathic interstitial pneumonia; dermatomyositis; the vitiligo vulgaris disease; ichthyosis vulgaris; photo-allergy sensitivity; cutaneous T cell lymphoma; arteriosclerosis; atherosclerosis; arteritis syndrome; polyarteritis nodosa; myocardosis; scleroderma; the Wei Genashi granuloma gangraenescens; sjogren's syndrome; obesity; the eosinocyte fascitis; gum; periodontal tissue; the infringement of alveolar bone; substantia ossea dentis; glomerulonephritis; male pattern alopecia or senile alopecia (by preventing alopecia or providing the hair rudiment and/or generation of promotion hair and natural on-off cycles of hair growth); muscular dystrophy; the assorted Reye syndrome of pyoderma and match; addisonian syndrome; in protection; the ischemia-reperfusion damage of the organ that takes place when transplanting or ischemic disease; endotoxin shock; pseudomembranous colitis; the colitis that causes by medicine or radiation; the ischemic acute renal insufficiency; chronic renal insufficiency; by lung-oxygen or drug induced toxinosis; pulmonary carcinoma; emphysema; cataract; arc-welder's disease; retinitis pigmentosa; senile degeneration of macula; the vitreal cicatrization; cornea highly basic burn; erythema multiforme dermatitis; linear IgA ballous dermatitis and cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; the disease that causes by environmental pollution; old and feeble; carcinogenesis; cancerometastasis and altitude sickness; discharge the disease that causes by histamine or leukotriene-C4; Behcet; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial hepatectomy; acute severe hepatitis; the necrosis that causes by toxin; viral hepatitis; shock; or anoxia; the B-viral hepatitis; non--A/ is non--hepatitis B; liver cirrhosis; alcoholic cirrhosis; liver failure; fulminant hepatic failure; the liver failure of late onset; " acute-on-chronic " liver failure; the reinforcement of chemotherapy effect; cytomegalovirus infection; HCMV infects; AIDS; cancer; alzheimer disease; wound and chronic bacterial infection.
15. the method for claim 11, wherein said immunoregulatory abnormality is selected from following disease:
1) multiple sclerosis,
2) rheumatoid arthritis,
3) systemic lupus erythematosus,
4) psoriasis,
5) repulsion of transplant organ or tissue,
6) inflammatory bowel,
7) malignant tumor in lymph source,
8) acute and chronic lymphocytic leukemia and lymphoma and
9) insulin and noninsulindependent diabetes.
16. an inhibition needs immune method in the immunosuppressant mammalian subject, described method comprises the chemical compound of using the claim 1 of immunosuppressant effective dose to described patient.
17. comprise the chemical compound of claim 1 and the pharmaceutical composition of pharmaceutically suitable carrier.
18. comprising with the amount that can effectively treat described respiratory disorder or disease, a method for the treatment of respiratory disorder in the mammalian subject that needs such treatment or disease, described method use the chemical compound of claim 1 for described patient.
19. the chemical compound of claim 18, wherein said respiratory disorder or disease are selected from following said method: asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, acidophil granuloma, respiratory syncytial virus bronchiolitis, bronchiectasis, idiopathic pulmonary fibrosis, acute lung injury and obstructive bronchiolitis are organized pneumonia.
20. treatment relates to the disease of vascular integrity or the method for disease in this patient who needs is arranged, wherein said disease or disease are selected from: angioedema, nodular vasculitis, the blood vessel injury that causes by ischemic diseases and thrombosis, ischemic enteropathy, inflammatory bowel, necrotizing enterocolitis, the damage of intestines that causes with thermal burn, arteriosclerosis, atherosclerosis, aortitis syndrome, in preservation, the ischemia reperfusion injury that takes place during transplanting or the ischemic diseases, endotoxin shock, pseudomembranous colitis, by medicine or radioactive colitis, ischemic acute renal insufficiency, chronic renal insufficiency, by lung oxygen or drug-induced toxinosis, sepsis, pancreatitis, discharge the disease that causes by histamine or leukotriene-C4, the necrosis that causes by toxin, viral hepatitis, shock or anoxia, senile dementia and wound, described method comprise the chemical compound of using the claim 1 of the amount that can effectively treat disease or disease to described patient.
21. treatment has among this patient who needs the method with brain or pulmonary edema diseases associated or disease, described method comprises the chemical compound of using the claim 1 of the amount that can effectively treat disease or disease to described patient.
22. the method for claim 21, wherein said disease or disease are selected from shock, sepsis, adult respiratory distress syndrome and cerebral edema.
CNA2005800362656A 2004-10-22 2005-10-18 2-(aryl)azacyclylmethyl carboxylates, sulfonates, phosphonates, phosphinates and heterocycles as s1p receptor agonists Pending CN101043887A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US62131304P 2004-10-22 2004-10-22
US60/621,313 2004-10-22

Publications (1)

Publication Number Publication Date
CN101043887A true CN101043887A (en) 2007-09-26

Family

ID=36228244

Family Applications (1)

Application Number Title Priority Date Filing Date
CNA2005800362656A Pending CN101043887A (en) 2004-10-22 2005-10-18 2-(aryl)azacyclylmethyl carboxylates, sulfonates, phosphonates, phosphinates and heterocycles as s1p receptor agonists

Country Status (7)

Country Link
US (1) US7659294B2 (en)
EP (1) EP1804793A4 (en)
JP (1) JP2008517915A (en)
CN (1) CN101043887A (en)
AU (1) AU2005299851B2 (en)
CA (1) CA2583681A1 (en)
WO (1) WO2006047195A2 (en)

Families Citing this family (68)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2007109207A (en) 2004-08-13 2008-09-20 Прикис Фамэсьютикэлс, Инк. (US) COMPOUNDS-MODULATORS OF Sphingosine-1-Phosphate Receptor Activity (OPTIONS), PHARMACEUTICAL COMPOSITION CONTAINING THE INDICATED COMPOUNDS, AND METHOD FOR TREATMENT OF DISORDERS, ASSOCIATED SECTION-1-Associated
BRPI0709866B8 (en) 2006-04-03 2021-05-25 Astellas Pharma Inc hetero compounds and pharmaceutical composition comprising said compounds
SI2069336T1 (en) 2006-09-07 2013-03-29 Actelion Pharmaceuticals Ltd. Pyridin-4-yl derivatives as immunomodulating agents
TWI408139B (en) 2006-09-07 2013-09-11 Actelion Pharmaceuticals Ltd Novel thiophene derivatives
MX2009002234A (en) 2006-09-08 2009-03-16 Actelion Pharmaceuticals Ltd Pyridin-3-yl derivatives as immunomodulating agents.
AU2007302262A1 (en) * 2006-09-29 2008-04-03 Novartis Ag Oxadiazole derivatives with anti-inflammatory and immunosuppressive properties
NZ577111A (en) 2006-12-15 2012-05-25 Abbott Lab Novel oxadiazole compounds
JO2701B1 (en) 2006-12-21 2013-03-03 جلاكسو جروب ليميتد Compounds
CA2678575C (en) * 2007-02-16 2013-10-08 Emisphere Technologies, Inc. Compounds having a cyclic moiety and compositions for delivering active agents
CN101627034B (en) 2007-03-16 2013-05-15 埃科特莱茵药品有限公司 Amino- pyridine derivatives as s1p1 /edg1 receptor agonists
CL2008001099A1 (en) 2007-04-19 2008-10-24 Glaxo Group Ltd COMPOUNDS DERIVED FROM INDAZOL; AND ITS USE TO TREAT DISEASES MEDIATED BY S1P1 RECEPTORS, SUCH AS MULTIPLE SCLEROSIS, AUTOIMMUNE DISEASE, INFLAMMATORY DISORDERS, DIABETES, BETWEEN OTHER.
BRPI0817597A2 (en) * 2007-10-04 2015-04-07 Merck Serono Sa Oxadiazole diaryl compounds, process for their preparation, pharmaceutical compositions and kit comprising them, as well as their uses
KR20100092473A (en) 2007-11-01 2010-08-20 액테리온 파마슈티칼 리미티드 Novel pyrimidine derivatives
GB0722340D0 (en) * 2007-11-14 2007-12-27 Univ Leiden Sphingosine-1-phosphate (S1P) receptor compounds
BRPI0820868A2 (en) 2007-12-10 2019-09-24 Actelion Pharmaceuticals Ltd thiophene compound formula (i), pharmaceutical composition containing it and use thereof for the prevention or treatment of diseases or disorders associated with an activated immune system
PE20091339A1 (en) 2007-12-21 2009-09-26 Glaxo Group Ltd OXADIAZOLE DERIVATIVES WITH ACTIVITY ON S1P1 RECEPTORS
GB0725102D0 (en) * 2007-12-21 2008-01-30 Glaxo Group Ltd Compounds
GB0725105D0 (en) 2007-12-21 2008-01-30 Glaxo Group Ltd Compounds
GB0725101D0 (en) 2007-12-21 2008-01-30 Glaxo Group Ltd Compounds
CN102007107B (en) 2008-03-07 2014-07-23 埃科特莱茵药品有限公司 Novel aminomethyl benzene derivatives
GB0807910D0 (en) * 2008-04-30 2008-06-04 Glaxo Group Ltd Compounds
WO2009153307A1 (en) * 2008-06-20 2009-12-23 Glaxo Group Limited Compounds
AU2009270511B2 (en) 2008-07-15 2013-07-18 Sanofi Oxazolopyrimidines as Edg-1 receptor agonists
EP2326621B1 (en) 2008-07-23 2016-06-08 Arena Pharmaceuticals, Inc. SUBSTITUTED 1,2,3,4- TETRAHYDROCYCLOPENTA[b]INDOL-3-YL) ACETIC ACID DERIVATIVES USEFUL IN THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISORDERS
JP5878015B2 (en) * 2008-07-23 2016-03-08 ノバルティス アーゲー Sphingosine monophosphate receptor modulators and their use to treat muscle inflammation
RS54970B1 (en) 2008-08-27 2016-11-30 Arena Pharm Inc Substituted tricyclic acid derivatives as s1p1 receptor agonists useful in the treatment of autoimmune and inflammatory disorders
AU2009327133B2 (en) 2008-12-18 2016-04-14 Merck Serono S.A. Oxadiazole fused heterocyclic derivatives useful for the treatment of multiple sclerosis
WO2010085584A1 (en) 2009-01-23 2010-07-29 Bristol-Myers Squibb Company Pyrazole-i, 2, 4 -oxad iazole derivatives as s.phing0sine-1-ph0sphate agonists
CN102361869A (en) 2009-01-23 2012-02-22 百时美施贵宝公司 Substituted oxadiazole derivatives as s1p agonists in the treatment of autoimmune and inflammatory diseases
WO2010085581A1 (en) 2009-01-23 2010-07-29 Bristol-Myers Squibb Company Substituted oxadiazole derivatives as s1p agonists in the treatment of autoimmune and inflammatory diseases
EP2435400A2 (en) 2009-05-27 2012-04-04 Leo Pharma A/S Novel calcium sensing receptor modulating compounds and pharmaceutical use thereof
EP2435404A1 (en) * 2009-05-27 2012-04-04 Leo Pharma A/S Novel calcium sensing receptor modulating compounds and pharmaceutical use thereof
GB0910674D0 (en) 2009-06-19 2009-08-05 Glaxo Group Ltd Novel compounds
PL2454255T3 (en) 2009-07-16 2014-04-30 Idorsia Pharmaceuticals Ltd Pyridin-4-yl derivatives as s1p1/edg1 agonists
US8399451B2 (en) 2009-08-07 2013-03-19 Bristol-Myers Squibb Company Heterocyclic compounds
AR077969A1 (en) * 2009-08-31 2011-10-05 Abbott Healthcare Products Bv DERIVATIVES OF (TIO) MORFOLINA COMOMODULADORES DE S1P
EP2592071B1 (en) 2009-10-29 2019-09-18 Bristol-Myers Squibb Company Tricyclic heterocyclic compounds
EP3378854B1 (en) 2010-01-27 2022-12-21 Arena Pharmaceuticals, Inc. Processes for the preparation of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetic acid and salts thereof
CA2789480A1 (en) 2010-03-03 2011-09-09 Arena Pharmaceuticals, Inc. Processes for the preparation of s1p1 receptor modulators and crystalline forms thereof
WO2011109650A1 (en) * 2010-03-03 2011-09-09 The Board Of Trustees Of The University Of Illinois Method of treating acute lung injury using sphingosine 1 phosphate analoges or sphingosine 1 phosphate receptor agonists
JP5735634B2 (en) 2010-04-23 2015-06-17 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 4- (5-Isoxazolyl or 5-pyrazolyl-1,2,4-oxadiazol-3-yl) -mandelic acid amide compounds as sphingosine-1-phosphate receptor 1 agonists
JP5712510B2 (en) * 2010-06-18 2015-05-07 Jnc株式会社 Compound having 5-membered ring, liquid crystal composition, and liquid crystal display device
TW201206893A (en) 2010-07-09 2012-02-16 Abbott Healthcare Products Bv Bisaryl (thio) morpholine derivatives as S1P modulators
TWI522361B (en) 2010-07-09 2016-02-21 艾伯維公司 Fused heterocyclic derivatives as s1p modulators
TW201643169A (en) 2010-07-09 2016-12-16 艾伯維股份有限公司 Spiro-piperidine derivatives as S1P modulators
EP2595969B1 (en) 2010-07-20 2015-04-22 Bristol-Myers Squibb Company Substituted 3-phenyl-1,2,4-oxadiazole compounds
WO2012040532A1 (en) 2010-09-24 2012-03-29 Bristol-Myers Squibb Company Substituted oxadiazole compounds and their use as s1p1 agonists
JP2013544811A (en) 2010-11-03 2013-12-19 ブリストル−マイヤーズ スクイブ カンパニー Heterocyclic compounds as S1P1 agonists for the treatment of autoimmune and vascular diseases
MY163185A (en) 2011-01-19 2017-08-15 Idorsia Pharmaceuticals Ltd 2-methoxy-pyridin-4-yl derivatives
AU2012354695B2 (en) * 2011-12-23 2016-11-03 Meiji Seika Pharma Co., Ltd. Novel S1P receptor modulator
US9505728B2 (en) 2012-03-09 2016-11-29 Inception 2, Inc. Triazolone compounds and uses thereof
MX2015007433A (en) 2012-12-20 2015-12-07 Inception 2 Inc Triazolone compounds and uses thereof.
US9115054B2 (en) 2013-02-21 2015-08-25 Bristol-Myers Squibb Company Tetrahydronaphthalenyl compounds useful as sipi agonists
WO2015035059A1 (en) 2013-09-06 2015-03-12 Inception 2, Inc. Triazolone compounds and uses thereof
MA40082B1 (en) 2014-08-20 2019-09-30 Bristol Myers Squibb Co New Sphingosine Phosphate Substitution Compound Useful Treatment Disease Rheumatism
AU2016205361C1 (en) 2015-01-06 2021-04-08 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
HUE047646T2 (en) 2015-05-20 2020-05-28 Idorsia Pharmaceuticals Ltd Crystalline form of the compound (s)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol
SI3310760T1 (en) 2015-06-22 2023-02-28 Arena Pharmaceuticals, Inc. Crystalline l-arginine salt of (r)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta(b)indol-3-yl)acetic acid for use in s1p1 receptor-associated disorders
WO2017004609A1 (en) * 2015-07-02 2017-01-05 Exelixis, Inc. Thiadiazole modulators of s1p and methods of making and using
US10633354B2 (en) 2016-09-02 2020-04-28 Bristol-Myers Squibb Company Substituted tricyclic heterocyclic compounds
KR20190116416A (en) 2017-02-16 2019-10-14 아레나 파마슈티칼스, 인크. Compounds and Methods for Treating Primary Bile Cholangitis
MA47503A (en) 2017-02-16 2021-04-21 Arena Pharm Inc COMPOUNDS AND METHODS FOR THE TREATMENT OF CHRONIC INFLAMMATORY DISEASES OF THE INTESTINE WITH EXTRAINTESTINAL MANIFESTATIONS
CN110945128B (en) 2017-04-14 2023-11-03 代表亚利桑那大学的亚利桑那董事会 Compositions and methods for treating pulmonary fibrosis
WO2018191747A1 (en) 2017-04-14 2018-10-18 Arizona Board Of Regents On Behalf Of The University Of Arizona Compositions and methods for treating pulmonary arterial hypertension
US11059784B2 (en) 2017-08-09 2021-07-13 Bristol-Myers Squibb Company Oxime ether compounds
WO2019032632A1 (en) 2017-08-09 2019-02-14 Bristol-Myers Squibb Company Alkylphenyl compounds
US11555015B2 (en) 2018-09-06 2023-01-17 Arena Pharmaceuticals, Inc. Compounds useful in the treatment of autoimmune and inflammatory disorders
JP2022553802A (en) 2019-10-31 2022-12-26 エスケープ・バイオ・インコーポレイテッド Solid Forms of S1P Receptor Modulators

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3974781B2 (en) * 2000-04-21 2007-09-12 塩野義製薬株式会社 Oxadiazole derivatives having anticancer activity
AU2003216054B2 (en) * 2002-01-18 2007-01-04 Merck & Co., Inc. Selective S1P1/Edg1 receptor agonists
EP1549640A4 (en) * 2002-06-17 2008-08-06 Merck & Co Inc 1-((5-aryl-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylates and 1-((5-aryl-1,2,4-oxadiazol-3-yl)benzyl)pyrrolidine-3-carboxylates as edg receptor agonists
AU2003279915A1 (en) * 2002-10-15 2004-05-04 Merck And Co., Inc. Process for making azetidine-3-carboxylic acid
EP1594508B1 (en) * 2003-02-11 2012-08-08 Irm Llc Novel bicyclic compounds and compositions

Also Published As

Publication number Publication date
AU2005299851A1 (en) 2006-05-04
WO2006047195A3 (en) 2007-03-22
AU2005299851B2 (en) 2011-03-17
EP1804793A4 (en) 2010-03-31
JP2008517915A (en) 2008-05-29
US7659294B2 (en) 2010-02-09
EP1804793A2 (en) 2007-07-11
WO2006047195A2 (en) 2006-05-04
CA2583681A1 (en) 2006-05-04
US20090042954A1 (en) 2009-02-12

Similar Documents

Publication Publication Date Title
CN101043887A (en) 2-(aryl)azacyclylmethyl carboxylates, sulfonates, phosphonates, phosphinates and heterocycles as s1p receptor agonists
CN1788008A (en) 3-(2-amino-1-azacyclyl)-5-aryl-1,2,4-oxadiazoles as S1P receptor agonists
CN1859908A (en) 3,5-aryl, heteroaryl or cycloalkyl substituted-1,2,4-oxadiazoles as S1P receptor agonists
CN1097051C (en) N-heteroaryl-pyridinesulfonamide derivatives and their use as endothelin antagonists
US7199142B2 (en) 1-((5-aryl-1,2,4-oxadiazol-3-yl) benzyl)azetidine-3-carboxylates and 1-((5-aryl-1,2,4-oxadiazol-3-yl)benzyl) pyrrolidine-3-carboxylates as edg receptor agonists
CN1036652C (en) Quaternary basic amides, method of preparing them and pharmaceutical compositions in which they are present
CN1216864C (en) Positive modulators of nicotinic receptor agonists
CN1630633A (en) N-biphenylmethyl aminocycloalkanecarboxamide derivatives with a substiituent on the methyl useful as bradykinin antagonists
CN1894225A (en) (3,4-disubstituted)propanoic carboxylates as SLP (EDG) receptor agonists
CN1675201A (en) N-substituted piperidine derivatives as serotonin receptor agents
CN1678578A (en) Indoles having anti-diabetic activity
CN1429215A (en) Triazole derivatives
CN1909902A (en) Triazole, oxadiazole and thiadiazole derivatives as PPAR modulators for the treatment of diabetes
CN1238689A (en) Vitronectin receptor antagonists
CN1589269A (en) Heteroindanes: a new class of potent cannabimimetic ligands
CN1150165C (en) 1-arenesulfonyl-2-aryl-pyrolidine and piperidine derivatives for treatment of CNS disorders
CN1845922A (en) Benzimidazolone compounds having 5-HT4 receptor agonistic activity
CN1136811A (en) Novel(R)-5-carbamyl-8-fluoro-3-N,N-disubstituted-amino-3,4-dihydro-2H-1-benzopyranes
CN1198803C (en) Heterocyclic compounds having effect of activating nicoting acetylchloine alpha 4 beta 2 receptor
CN1788002A (en) Biaryl substituted triazoles as sodium channnel blockers
CN1930146A (en) Piperidinylcarbonyl-pyrrolidines and their use as melanocortin agonists
CN1189823A (en) Cyclic amidino agents useful as nitric oxide synthase inhibitors
CN102395584A (en) Compounds for the treatment of metabolic disorders
CN1777609A (en) 2-alkynyl-and 2-alkenyl-pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]-pyrimidine adenosine a2a receptor antagonists
CN1893825A (en) Substituted arylpyrazoles as parasiticidal agents

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C02 Deemed withdrawal of patent application after publication (patent law 2001)
WD01 Invention patent application deemed withdrawn after publication

Open date: 20070926